Quinolone compound and pharmaceutical composition

ABSTRACT

The present invention provides a quinolone compound represented by General Formula (1) 
                         
or a salt thereof, wherein R 1  represents a hydrogen atom, etc.; R 2  represents a hydrogen atom, etc.; R 3  represents a phenyl group optionally being substituted with one or more substituents, etc.; R 4  represents a halogen atom; R 5  represents a hydrogen atom or halogen atom; R 6  represents a hydrogen atom; and R 7  represents a hydroxyl group, etc. The quinolone compound have a functional improvement effect, which suppresses progression of neurological dysfunction by inhibiting the chronic progression of Parkinson&#39;s disease or protecting dopamine neurons from the disease etiology, thereby prolonging the period before first administration begins.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.12/599,003 filed Jan. 12, 2010, which is a 371 National StageApplication of PCT/JP2008/060804 filed Jun. 6, 2008, which claimsbenefit of Japanese Application No. 2007-150819 filed Jun. 6, 2007. Theabove applications are incorporated herein by reference in theirentirety.

TECHNICAL FIELD

The present invention relates to a quinolone compound and apharmaceutical composition.

BACKGROUND ART

Parkinson's disease is a chronic, progressive neurodegenerative diseasethat generally develops after middle age. Initial symptoms includeunilateral resting tremor, akinesia and rigidity. The tremors, akinesia,and rigidity are called the three major signs of Parkinson's disease,and each of them are caused by the selective death of dopaminergicneurons projected from the substantia nigra to the striatum. Theetiology of the disease is still unknown; however, accumulated evidencesuggests that an impaired energy-generating system accompanied byabnormal mitochondrial function of nigrostriatal dopaminergic neuronstriggers the neurodegenerative disorder of the disease. Themitochondrial dysfunction has been assumed to subsequently causeoxidative stress and failure of calcium homeostasis, thereby resultingin neurodegeneration (Ann. N.Y. Acad. Sci. 991:111-119 (2003)).

Treatments of Parkinson's disease are roughly classified into medicalmanagement (medication) and surgical management (stereotaxic operation).Of these, medication is an established therapy and regarded as a basictreatment. In the medication, a symptomatic therapeutic agent is used tocompensate for the nigrostriatal dopaminergic neuronal functiondenatured by Parkinson's disease. L-dopa exhibits the most remarkabletherapeutic effects. It is said that no agent exceeds the effectivenessof L-dopa. Currently, L-dopa is used together with a dopa decarboxylaseinhibitor to prevent the metabolism thereof in the periphery, and thedesired clinical effects have been obtained.

However, one disadvantage of the L-dopa treatment is that after severalyears of usage, the decrement of the durability and stability of thedrug's efficacy results in the recurrence of movement disorders such asdyskinesia and daily fluctuation. Moreover, digestive side effects suchas nausea and vomiting brought on by the excess release of dopamine,circulatory organ problems such as orthostatic hypotension, tachycardiaand arrhythmia, and neurological manifestations such as hallucinations,delusions and distractions have been a cause for concern.

Thus, in order to decrease the L-dopa preparation dosage and therebyreducing the side effects, multidrug therapies, in which dopaminereceptor agonists, dopamine metabolism enzyme inhibitors, dopaminereleaser, central anticholinergic agents and the like are used incombination, are employed. Such therapeutic advances remarkably improveprognoses; even now, however, there is no fundamental cure forParkinson's disease and other neurodegenerative diseases. Medicationmust be taken for the rest of the patient's life, and the aforementioneddrawbacks—decreased efficacy during long-term administration, sideeffects, and uncontrollable disease progression—can result from L-dopamonotherapy. In addition, it is difficult to expect dramatic effects,even during the employment of multidrug therapies.

DISCLOSURE OF THE INVENTION

The present invention aims to provide a novel compound that has afunctional improvement effect and suppresses of neurological dysfunctionby inhibiting the chronic progression of Parkinson's disease orprotecting dopamine neurons from the disease etiology, therebyprolonging the period before first L-dopa administration begins.

The present inventors carried out extensive research to accomplish theaforementioned object, and as a result, they succeeded in producing acompound represented by the following General Formula (1), whichcomprises protecting and improving mitochondrial functional activity,and protecting and repairing neuron activity. The present invention hasbeen accomplished based on the above findings.

The present invention provides a quinolone compound, a pharmaceuticalcomposition comprising said compound, a use of said compound, a methodfor treating or preventing a disorder, and a process for producing saidcompound, as descrived in Item 1 to 11 below.

Item 1. A quinolone compound represented by General Formula (1)

or a salt thereof,

wherein R₁ represents a hydrogen atom, a lower alkyl group, a cyclo C₃₋₈alkyl lower alkyl group, or a lower alkoxy lower alkyl group;

R₂ represents a hydrogen atom, a lower alkyl group, or ahalogen-substituted lower alkyl group;

R₃ represents a phenyl group, a furyl group, a thienyl group, or apyridyl group, each of the groups optionally being substituted with oneor more groups selected from the group consisting of the following (1)to (16) on the aromatic or heterocyclic ring represented by the aboveR₃:

-   (1) lower alkyl groups,-   (2) lower alkoxy groups,-   (3) halogen-substituted lower alkoxy groups,-   (4) a phenoxy group,-   (5) lower alkylthio groups,-   (6) a hydroxy group,-   (7) hydroxy lower alkyl groups,-   (8) halogen atoms,-   (9) lower alkanoyl groups,-   (10) lower alkoxycarbonyl groups,-   (11) amino groups optionally substituted with one or more lower    alkyl groups,-   (12) carbamoyl groups optionally substituted with one or more lower    alkyl groups,-   (13) cyclo C₃₋₈ alkyl lower alkoxy groups,-   (14) pyrrolidinyl carbonyl groups,-   (15) morpholinyl carbonyl groups, and-   (16) a carboxyl group;

R₄ represents a halogen atom;

R₅ represents a hydrogen atom or a halogen atom;

R₆ represents a hydrogen atom; and

R₇ represents any one of groups (1) to (15) below:

-   (1) a hydroxy group,-   (2) a halogen atom,-   (3) a lower alkoxy group,-   (4) a halogen-substituted lower alkoxy group,-   (5) a hydroxy lower alkoxy group,-   (6) a lower alkoxy lower alkoxy group,-   (7) an amino group optionally substituted with one or more members    selected from the group consisting of lower alkyl groups, lower    alkoxy lower alkyl groups, and cyclo C₃₋₈ alkyl groups,-   (8) an amino lower alkoxy group optionally substituted on the amino    group with one or more members selected from the group consisting of    lower alkyl groups, lower alkanoyl groups, lower alkyl sulfonyl    groups, and carbamoyl groups optionally substituted with one or more    lower alkyl groups,-   (9) a cyclo C₃₋₈ alkyloxy group,-   (10) a cyclo C₃₋₈ alkyl lower alkoxy group,-   (11) a tetrahydrofuryl lower alkoxy group,-   (12) a lower alkylthio group,-   (13) a heterocyclic group selected from the group consisting of    morpholinyl groups, pyrrolidinyl groups, furyl groups, thienyl    groups, and benzothienyl groups,-   (14) a phenyl lower alkoxy lower alkoxy group, and-   (15) a pyrrolidinyl carbonyl group.

Item 2. A quinolone compound of General Formula (1) or a salt thereofaccording to item 1,

wherein R₁ represents a hydrogen atom or a lower alkyl group;

R₂ represents a hydrogen atom or a lower alkyl group;

R₃ represents a phenyl group or a pyridyl group, each of the groupsoptionally being substituted with one or two groups selected from thegroup consisting of the following (1), (2), (6), and (8) on the aromaticor heterocyclic ring represented by the above R₃:

-   (1) lower alkyl groups,-   (2) lower alkoxy groups,-   (6) a hydroxy group, and-   (8) halogen atoms;

R₄ represents a halogen atom;

R₅ represents a hydrogen atom;

R₆ represents a hydrogen atom; and

R₇ represents any one of groups (3), (4), and (7) below:

-   (3) a lower alkoxy group,-   (4) a halogen-substituted lower alkoxy group, and-   (7) an amino group optionally substituted with one or two lower    alkyl groups

Item 3. A quinolone compound of General Formula (1) or a salt thereofaccording to item 2 selected from the group consisting of:

-   5-fluoro-3-(4-methoxyphenyl)-2-methyl-8-propoxy-1H-quinolin-4-one,-   5-fluoro-3-(4-methoxyphenyl)-1-methyl-8-propoxy-1H-quinolin-4-one,-   3-(2,4-dimethoxyphenyl)-5-fluoro-8-propoxy-1H-quinolin-4-one,-   5-fluoro-8-isopropoxy-3-(4-methoxyphenyl)-1H-quinolin-4-one,-   3-(2,4-dichlorophenyl)-5-fluoro-8-propoxy-1H-quinolin-4-one,-   8-ethoxy-5-fluoro-3-(4-methoxyphenyl)-1H-quinolin-4-one,-   5-fluoro-3-(4-methoxy-2-methylphenyl)-8-propoxy-1H-quinolin-4-one,-   5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one,-   5-fluoro-3-(2-fluoro-4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one,-   5-fluoro-3-(4-hydroxyphenyl)-8-propoxy-1H-quinolin-4-one,-   8-cyclopropylmethoxy-5-fluoro-3-(4-methoxyphenyl)-1H-quinolin-4-one,-   5-fluoro-8-propoxy-3-pyridin-4-yl-1H-quinolin-4-one,-   5-fluoro-3-(4-methoxyphenyl)-8-(N-methyl-N-propylamino)-1H-quinolin-4-one,    and-   5-fluoro-3-(4-methoxyphenyl)-8-(4,4,4-trifluorobutoxy)-1H-quinolin-4-one.

Item 4. A pharmaceutical composition comprising a quinolone compound ofGeneral Formula (1) or a salt thereof according to item 1 as an activeingredient and a pharmaceutically acceptable carrier.

Item 5. A prophylactic and/or therapeutic agent for neurodegenerativediseases, diseases induced by neurological dysfunction, or diseasesinduced by deterioration of mitochondrion function, comprising as anactive ingredient a quinolone compound of General Formula (1) or a saltthereof according to item 1.

Item 6. A prophylactic and/or therapeutic agent according to item 5,wherein the neurodegenerative disease is selected from the groupconsisting of Parkinson's disease, Parkinson's syndrome, juvenileparkinsonism, striatonigral degeneration, progressive supranuclearpalsy, pure akinesia, Alzheimer's disease, Pick's disease, priondisease, corticobasal degeneration, diffuse Lewy body disease,Huntington's disease, chorea-acanthocytosis, benign hereditary chorea,paroxysmal choreoathetosis, essential tremor, essential myoclonus,Gilles de la Tourette's syndrome, Rett's syndrome, degenerative ballism,dystonia musculorum deformance, athetosis, spasmodic torticollis, Meigesyndrome, cerebral palsy, Wilson's disease, Segawa's disease,Hallervorden-Spatz syndrome, neuroaxonal dystrophy, pallidal atrophy,spino-cerebellar degeneration, cerebral cortical atrophy, Holmes-typecerebellar atrophy, olivopontocerebellar atrophy, hereditaryolivopontocerebellar atrophy, Joseph disease, dentatorubropallidoluysianatrophy, Gerstmann-Straussler-Scheinker disease, Friedreich's Ataxia,Roussy-Levy syndrome, May-White syndrome, congenital cerebellar ataxia,hereditary episodic ataxia, ataxia telangiectasia, amyotrophic lateralsclerosis, progressive bulbar palsy, spinal progressive muscularatrophy, spinobulbar muscular atrophy, Werdnig-Hoffmann disease,Kugelberg-Welander disease, hereditary spastic paraparesis,syringomyelia, syringobulbia, Arnold-Chiari malformation, Stiffmansyndrome, Klippel-Feil syndrome, Fazio-Londe syndrome, lower myelopathy,Dandy-Walker syndrome, spina bifida, Sjogren-Larsson syndrome, radiationmyelopathy, age-related macular degeneration, and cerebral apoplexyselected from the group consisting of cerebral infarction and cerebralhemorrhage.

Item 7. A prophylactic and/or therapeutic agent according to item 5,wherein the disease induced by neurological dysfunction is selected fromthe group consisting of spinal cord injury, chemotherapy-inducedneuropathy, diabetic neuropathy, radiation damage, and demyelinatingdiseases selected from the group consisting of multiple sclerosis, acutedisseminated encephalomyelitis, transverse myelitis, progressivemultifocal leucoencephalopathy, subacute sclerosing panencephalitis,chronic inflammatory demyelinating polyneuropathy and Guillain-Barresyndrome.

Item 8. A prophylactic and/or therapeutic agent according to item 5,wherein the disease induced by deterioration of mitochondrion functionis selected from the group consisting of Pearson's syndrome, diabetes,deafness, malignant migraine, Leber's disease, MELAS, MERRF, MERRF/MELASoverlap syndrome, NARP, pure myopathy, mitochondrial cardiomyopathy,myopathy, dementia, gastrointestinal ataxia, acquired sideroblasticanemia, aminoglycoside-induced hearing loss, complex III deficiency dueto inherited variants of cytochrome b, multiple symmetrical lipomatosis,ataxia, myoclonus, retinopathy, MNGIE, ANTI disease, Twinkle disease,POLG disease, recurrent myoglobinuria, SANDO, ARCO, complex Ideficiency, complex II deficiency, optic nerve atrophy, fatal infantilecomplex IV deficiency, mitochondrial DNA deficiency, mitochondrial DNAdeficiency syndrome, Leigh's encephalomyelopathy,chronic-progressive-external-ophthalmoplegia syndrome (CPEO),Kearns-Sayre syndrome, encephalopathy, lactacidemia, myoglobinuria,drug-induced mitochondrial diseases, schizophrenia, major depressiondisorder, bipolar I disorder, bipolar II disorder, mixed episode,dysthymic disorders, atypical depression, seasonal affective disorders,postpartum depression, minor depression, recurrent brief depressivedisorder, intractable depression/chronic depression, double depressionand acute renal failure.

Item 9. Use of a quinolone compound of General Formula (1) or a saltthereof according to item 1 as a drug.

Item 10. A method for treating or preventing neurodegenerative diseases,diseases induced by neurological dysfunction, or diseases induced bydeterioration of mitochondrion function, comprising administering aquinolone compound of General Formula (1) or a salt thereof according toitem 1 to a human or an animal.

Item 11. A process for producing a quinolone compound of General Formula(1)

or a salt thereof, wherein R₁, R₂, R₃, R₄, R₅, R₆ and R₇ are eachdefined above in item 1, comprising reacting a compound represented byGeneral Formula (4)

wherein R₁, R₄, R₅, R₆ and R₇ are each defined above in item 1, with acompound represented by General Formula (5)

wherein R₂ and R₃ are each defined above in item 1, and R₈ represents alower alkoxy group, thereby giving an intermediate compound representedby General Formula (6)

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇ and R₈ are each defined above; andsubjecting the resulting compound to a cyclization reaction.

Specific examples of groups in General Formula (1) are as follows.

Examples of lower alkyl groups include straight or branched C₁₋₆(preferably C₁₋₄) alkyl groups such as methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl,1-ethylpropyl, isopentyl, neopentyl, n-hexyl, 1,2,2-trimethylpropyl,3,3-dimethylbutyl, 2-ethylbutyl, isohexyl, 3-methylpentyl, etc.

Examples of C₃₋₈ cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.

Examples of cyclo C₃₋₈ alkyl lower alkyl groups include the lower alkylgroups substituted with one to three (preferably one) cyclo C₃₋₈ alkylgroup(s) described above.

Examples of lower alkoxy groups include straight or branched C₁₋₆(preferably C₁₋₄) alkoxy groups such as methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentyloxy,isopentyloxy, neopentyloxy, n-hexyloxy, isohexyloxy, 3-methylpentyloxy,etc.

Examples of lower alkoxy lower alkyl groups include the lower alkylgroups substituted with one to three (preferably one) lower alkoxygroup(s) described above.

Examples of halogen atoms include fluorine, chlorine, bromine, andiodine.

Examples of halogen-substituted lower alkyl groups include the loweralkyl groups substituted with one to seven halogen atom(s), preferablyone to three halogen atom(s). Examples thereof include fluoromethyl,difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,trichloromethyl, bromomethyl, dibromomethyl, dichlorofluoromethyl,2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl,2-fluoroethyl, 2-chloroethyl, 3,3,3-trifluoropropyl, heptafluoropropyl,2,2,3,3,3-pentafluoropropyl, heptafluoroisopropyl, 3-chloropropyl,2-chloropropyl, 3-bromopropyl, 4,4,4-trifluorobutyl,4,4,4,3,3-pentafluorobutyl, 4-chlorobutyl, 4-bromobutyl, 2-chlorobutyl,5,5,5-trifluoropentyl, 5-chloropentyl, 6,6,6-trifluorohexyl,6-chlorohexyl, perfluorohexyl, etc.

Examples of halogen-substituted lower alkoxy groups include the loweralkoxy groups substituted with one to seven halogen atom(s), preferablyone to three halogen atom(s). Examples thereof include fluoromethoxy,difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy,trichloromethoxy, bromomethoxy, dibromomethoxy, dichlorofluoromethoxy,2,2,2-trifluoroethoxy, pentafluoroethoxy, 2-chloroethoxy,3,3,3-trifluoropropoxy, heptafluoropropoxy, heptafluoroisopropoxy,3-chloropropoxy, 2-chloropropoxy, 3-bromopropoxy, 4,4,4-trifluorobutoxy,4,4,4,3,3-pentafluorobutoxy, 4-chlorobutoxy, 4-bromobutoxy,2-chlorobutoxy, 5,5,5-trifluoropentoxy, 5-chloropentoxy,6,6,6-trifluorohexyloxy, 6-chlorohexyloxy, etc.

Examples of lower alkylthio groups include alkylthio groups wherein thealkyl moiety is the lower alkyl group mentioned above.

Examples of hydroxy lower alkyl groups include the above-mentioned loweralkyl groups substituted with one to three (preferably one) hydroxygroup(s).

Examples of lower alkanoyl groups include straight or branched C₁₋₆(preferably C₁₋₄) alkanoyl groups such as formyl, acetyl, propionyl,butyryl, isobutyryl, pentanoyl, tert-butylcarbonyl, hexanoyl, etc.

Examples of lower alkoxycarbonyl groups include alkoxycarbonyl groupswherein the alkoxy moiety is the lower alkoxy group mentioned above.

Examples of amino groups optionally substituted with one or more loweralkyl groups include amino groups optionally substituted with one or twolower alkyl group(s) described above.

Examples of carbamoyl groups optionally substituted with one or morelower alkyl groups include carbamoyl groups optionally substituted withone or two lower alkyl group(s) described above.

Examples of cyclo C₃₋₈ alkyl lower alkyl groups include theabove-mentioned lower alkyl groups substituted with one to three(preferable one) cyclo C₃₋₈ alkyl group(s) described above.

Examples of hydroxy lower alkoxy groups include the above-mentionedlower alkoxy groups substituted with one to three (preferably one)hydroxy group(s).

Examples of lower alkoxy lower alkoxy groups include the above-mentionedlower alkoxy groups substituted with one to three (preferably one) loweralkoxy group(s) described above.

Examples of amino groups optionally substituted with one or more membersselected from the group consisting of lower alkyl groups, lower alkoxylower alkyl groups, and cyclo C₃₋₈ alkyl groups include amino groupsoptionally substituted with one or two members selected from the groupconsisting of the above-mentioned lower alkyl groups, theabove-mentioned lower alkoxy lower alkyl groups, and the above-mentionedcyclo C₃₋₈ alkyl groups.

Examples of lower alkyl sulfonyl groups include alkyl sulfonyl groupswherein the alkyl moiety is the lower alkyl group mentioned above.

Examples of amino lower alkoxy groups optionally substituted on an aminogroup with one or more members selected from the group consisting oflower alkyl groups, lower alkanoyl groups, lower alkyl sulfonyl groups,and carbamoyl groups optionally substituted with one or more lower alkylgroups include the lower alkoxy groups substituted with one to three(preferably one) amino group(s). Here, the amino lower alkoxy group isoptionally substituted on an amino group with one or two membersselected from the group consisting of the above-mentioned lower alkylgroups, the above-mentioned lower alkanoyl groups, the above-mentionedlower alkyl sulfonyl groups, carbamoyl groups optionally substitutedwith one or more lower alkyl groups mentioned above.

Examples of cyclo C₃₋₈ alkyloxy groups include groups in which the cycloC₃₋₈ alkyl group and an oxygen atom are bonded.

Examples of tetrahydrofuryl lower alkoxy groups include theabove-mentioned lower alkoxy groups substituted with one to three(preferably one) tetrahydrofuryl group(s).

Examples of lower alkylthio groups include alkylthio groups wherein thealkyl moiety is the lower alkyl group mentioned above.

Examples of phenyl lower alkoxy groups include the above-mentioned loweralkoxy groups substituted with one to three (preferably one) phenylgroup(s).

Examples of phenyl lower alkoxy lower alkoxy groups include theabove-mentioned lower alkoxy groups substituted with one to three phenyllower alkoxy group(s) (preferably one) described above.

The process of producing the compound of the invention is describedbelow in detail.

The quinolone compound represented by General Formula (1) (hereinafteralso referred to as Compound (1)) can be produced by various methods;for example, by a method according to the following Reaction Scheme 1 or2.

wherein R₁, R₂, R₃, R₄, R₅, R₆, and R₇ are as defined above, and X₁represents a halogen atom.

Examples of halogen atoms represented by X₁ include fluorine, chlorine,bromine, and iodine.

Preferable leaving groups in the reaction include halogen. Among these,iodine is particularly preferable.

Compound (1) can be prepared by reacting the compound of General Formula(2) and the compound of General Formula (3) in an inert solvent orwithout using any solvents, in the presence or absence of a basiccompound, in the presence of a palladium catalyst.

Examples of inert solvents include water; ether-based solvents such asdioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, diethyleneglycol dimethyl ether, and ethylene glycol dimethyl ether; aromatichydrocarbon-based solvents such as benzene, toluene, and xylene; loweralcohol-based solvents such as methanol, ethanol, and isopropanol;ketone-based solvents such as acetone and methyl ethyl ketone; and polarsolvents such as N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO),hexamethylphosphoric triamide, and acetonitrile. These inert solventscan be used singly or in combinations of two or more.

Palladium compounds used in the reaction are not particularly limited,but include, for example, tetravalent palladium catalysts such as sodiumhexachloropalladiumate (IV) tetrahydrate and potassiumhexachloropalladiumate (IV); divalent palladium catalysts such aspalladium (II) chloride, palladium (II) bromide, palladium (II) acetate,palladium (II) acetylacetonato, dichlorobis(benzonitrile)palladium (II),dichlorobis(acetonitrile)palladium (II),dichlorobis(triphenylphosphine)palladium (II), dichlorotetraamminepalladium (II), dichloro(cycloocta-1,5-diene)palladium (II), palladium(II) trifluoroacetate, and 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium (II)-dichloromethane complex; zerovalent palladiumcatalysts such as tris(dibenzylideneacetone)₂ palladium (0),tris(dibenzylideneacetone)₂ palladium (0) chloroform complex, andtetrakis(triphenylphosphine)palladium (0), etc. These palladiumcompounds are used singly or in combinations of two or more.

In the reaction, the amount of the palladium catalyst is notparticularly limited, but is typically in the range from 0.000001 to 20moles in terms of palladium relative to 1 mol of Compound (2). Theamount of the palladium catalyst is preferably in the range from 0.0001to 5 moles in terms of palladium relative to 1 mol of Compound (2).

This reaction advantageously proceeds in the presence of a suitableligand. Examples of ligands of the palladium catalyst include, forexample, 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl(BINAP),tri-o-tolylphosphine, bis(diphenylphosphino)ferrocene,triphenylphosphine, tri-t-butylphosphine, and9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (XANTPHOS). Theseligands are used singly or in combinations of two or more.

The proportion of the palladium catalyst and ligand is not particularlylimited. The amount of the ligand is about 0.1 to about 100 moles permole of the palladium catalyst, and preferably about 0.5 to about 15moles per mole of the palladium catalyst.

Various known inorganic and organic bases can be used as basiccompounds.

Inorganic bases include, for example, alkali metal hydroxides such assodium hydroxide, potassium hydroxide, cesium hydroxide, and lithiumhydroxide; alkali metal carbonates such as sodium carbonate, potassiumcarbonate, cesium carbonate, and lithium carbonate; alkali metalhydrogencarbonates such as lithium hydrogencarbonate, sodiumhydrogencarbonate, and potassium hydrogencarbonate; alkali metals suchas sodium and potassium; phosphates such as sodium phosphate andpotassium phosphate; amides such as sodium amide; and alkali metalhydrides such as sodium hydride and potassium hydride.

Organic bases include, for example, alkali metal lower alkoxides such assodium methoxide, sodium ethoxide, sodium t-butoxide, potassiummethoxide, potassium ethoxide, and potassium t-butoxide, and amines suchas triethylamine, tripropylamine, pyridine, quinoline, piperidine,imidazole, N-ethyldiisopropylamine, dimethylaminopyridine,trimethylamine, dimethylaniline, N-methylmorpholine,1,5-diazabicyclo[4.3.0]non-5-ene (DBN),1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane(DABCO), etc.

Such basic compounds can be used singly or in combinations of two ormore. More preferable basic compounds used in the reaction includealkali metal carbonates such as sodium carbonate, potassium carbonate,cesium carbonate, and lithium carbonate.

A basic compound is usually used in an amount of 0.5 to 10 moles permole of Compound (2), and preferably 0.5 to 6 moles per mole of Compound(2).

Compound (3) is usually used in an amount of at least about 1 mole permole of Compound (2), and preferably about 1 to about 5 moles per moleof Compound (2).

The reaction can be conducted under normal pressure, under inert gasatmospheres including nitrogen, argon, etc., or under increasedpressure.

The reaction proceeds usually at room temperature to 200° C., andpreferably at room temperature to 150° C., and is usually completed inabout 1 to about 30 hours. The reaction is also achieved by heating at100 to 200° C. for 5 minutes to 1 hour using a microwave reactor.

The compound represented by General Formula (3), which is used as astarting material in Reaction Scheme 1 is an easily available knowncompound. The compound represented by General Formula (2) includes anovel compound, and the compound is produced in accordance with ReactionScheme 6 shown below.

wherein R₁, R₂, R₃, R₄, R₅, R₆, and R₇ are as defined above, and R₈represents a lower alkoxy group.

The lower alkoxy group represented by R₈ in General Formula (5) has thesame definition as described above.

The compounds represented by General Formulae (4) and (5) are reacted inan inert solvent or without using any solvents, in the presence orabsence of an acid catalyst, thereby giving an intermediate compoundrepresented by General Formula (6). Then, the resulting compound wascyclized to produce the compound represented by General Formula (1).

Examples of inert solvents include water; ether-based solvents such asdioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, diethyleneglycol dimethyl ether, and ethylene glycol dimethyl ether; aromatichydrocarbon-based solvents such as benzene, toluene, and xylene; loweralcohol-based solvents such as methanol, ethanol, and isopropanol; andpolar solvents such as N,N-dimethylformamide (DMF), dimethyl sulfoxide(DMSO), hexamethylphosphoric triamide, and acetonitrile. These inertsolvents can be used singly or in combinations of two or more.

Various kinds of known acid catalysts can be used, includingtoluenesulfonic acid, methanesulfonic acid, xylene sulfonic acid,sulfuric acid, glacial acetic acid, boron trifluoride, acidic ionexchangers, etc. These acid catalysts can be used singly or incombinations of two or more.

Among such acids, acidic ion exchangers are preferably used. Examples ofacidic ion exchangers include polymeric cation exchangers available fromthe market such as Lewatit 5100, Zeo-karb 225, Dowex 50, AmberliteIR120, or Amberlyst 15 and like styrene sulfonic acid polymers; LewatitPN, Zeo-karb 215 or 315, and like polysulfonic acid condensates; LewatitCNO, Duolite CS100, and like m-phenolic carboxylic acid resins; orPermutit C, Zeo-karb 226 or Amberlite IRC 50, and like polyacrylates. Ofthese, Amberlyst 15 is particularly preferred.

An oxide catalyst is usually used in an amount of 0.0001 to 100 molesper mole of Compound (4), and preferably 0.5 to 6 moles per mole ofCompound (4).

In Reaction Scheme 2, Compound (5) is usually used in an amount of atleast about 1 mole per mole of Compound (4), and preferably about 1 toabout 5 moles per mole of Compound (4).

The reaction can be conducted under normal pressure, under inert gasatmospheres including nitrogen, argon, etc., or under increasedpressure.

The reaction proceeds usually at room temperature to 200° C., andpreferably at room temperature to 150° C. During the reaction,azeotropic removal of water is conducted until the reaction watergeneration is completed. The reaction is usually finished in about 1 toabout 30 hours.

The process of producing the compound of General Formula (1) via acyclization reaction of the intermediate compound represented by GeneralFormula (6) can be employed by heating the compound in a solvent such asdiphenyl ether, or by heating the compound in the absence of a solvent.The reaction is conducted at 150 to 300° C. for 5 minutes to 2 hours.

The compound represented by General Formula (4), used as a startingmaterial in Reaction Scheme 2 described above is a known compound or canbe produced easily using a known compound. The compound represented byGeneral Formula (5) includes a novel compound, and the compound ismanufactured in accordance with, for example, the methods shown inReaction Scheme 4 and Reaction Scheme 5 described above.

wherein R₂, R₃, R₄, R₅, R₆, and R₇ are as defined above, and R₁′ is agroup represented by R₁ other than hydrogen, and X₂ represents a groupthat undergoes the same substitution reaction as that of a halogen or ahalogen atom.

Halogens represented by X₂ in General Formula (1a) include the halogenatom described above. Groups that undergo the same substitution reactionas that of the halogen atoms represented by X₂ include lower alkylsulfonyloxy groups, aryl sulfonyloxy groups, aralkyl sulfonyloxy groups,etc.

Examples of lower alkyl sulfonyloxy groups include straight or branchedC₁₋₆ alkyl sulfonyloxy groups, such as methane sulfonyloxy, ethanesulfonyloxy, n-propane sulfonyloxy, isopropane sulfonyloxy, n-butanesulfonyloxy, tert-butane sulfonyloxy, n-pentane sulfonyloxy, andn-hexane sulfonyloxy.

Examples of aryl sulfonyloxy groups include naphthyl sulfonyloxy andphenyl sulfonyloxy optionally substituted on a phenyl ring with one tothree group(s) selected from the group consisting of straight orbranched C₁₋₆ alkyl groups, straight or branched C₁₋₆ alkoxy groups,nitro groups, and halogen atoms as a substituent. Examples of phenylsulfonyloxy groups optionally substituted with the above substituent(s)include phenyl sulfonyloxy, 4-methylphenyl sulfonyloxy, 2-methylphenylsulfonyloxy, 4-nitrophenyl sulfonyloxy, 4-methoxyphenyl sulfonyloxy,2-nitrophenyl sulfonyloxy, 3-chlorophenyl sulfonyloxy, etc. Examples ofnaphthyl sulfonyloxy groups include α-naphthyl sulfonyloxy, β-naphthylsulfonyloxy, etc.

Examples of aralkyl sulfonyloxy groups include phenyl-substitutedstraight or branched C₁₋₆ alkyl sulfonyloxy groups that may have, on thephenyl ring, one to three substituent(s) selected from the groupconsisting of straight or branched C₁₋₆ alkyl groups, straight orbranched C₁₋₆ alkoxy groups, a nitro group and halogen atoms as asubstituent, or naphtyl-substituted straight or branched C₁₋₆ alkylsulfonyloxy groups. Examples of alkyl sulfonyloxy groups substitutedwith the above-mentioned phenyl group(s) include benzyl sulfonyloxy,2-phenylethyl sulfonyloxy, 4-phenylbutyl sulfonyloxy, 4-methylbenzylsulfonyloxy, 2-methylbenzyl sulfonyloxy, 4-nitrobenzyl sulfonyloxy,4-methoxybenzyl sulfonyloxy, 3-chlorobenzyl sulfonyloxy, etc. Examplesof alkyl sulfonyloxy groups substituted with the above-mentionednaphthyl group(s) include α-naphthylmethyl sulfonyloxy, β-naphthylmethylsulfonyloxy, etc.

The compound represented by General Formula (1b) can be produced by thereaction of the compound represented by General Formula (1a) with thecompound represented by General Formula (7) in an inert solvent orwithout using any solvents, in the presence or absence of a basiccompound.

Examples of inert solvents include water; ether-based solvents such asdioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, diethyleneglycol dimethyl ether, and ethylene glycol dimethyl ether; aromatichydrocarbon-based solvents such as benzene, toluene, and xylene; loweralcohol-based solvents such as methanol, ethanol, and isopropanol;ketone-based solvents such as acetone and methyl ethyl ketone; and polarsolvents such as N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO),hexamethylphosphoric triamide, and acetonitrile. These inert solventscan be used singly or in combinations of two or more.

As a basic compound, various known inorganic bases and organic bases canbe used.

Inorganic bases include, for example, alkali metal hydroxides such assodium hydroxide, potassium hydroxide, cesium hydroxide, and lithiumhydroxide; alkali metal carbonates such as sodium carbonate, potassiumcarbonate, cesium carbonate, and lithium carbonate; alkali metalhydrogen carbonates such as lithium hydrogen carbonate, sodium hydrogencarbonate, and potassium hydrogen carbonate; alkali metals such assodium and potassium; amides such as sodium amide; and alkali metalhydrides such as sodium hydride and potassium hydride.

Organic bases include, for example, alkali metal lower alkoxides such assodium methoxide, sodium ethoxide, sodium t-butoxide, potassiummethoxide, potassium ethoxide, and potassium t-butoxide, and amines suchas triethylamine, tripropylamine, pyridine, quinoline, piperidine,imidazole, N-ethyl diisopropylamine, dimethylaminopyridine,trimethylamine, dimethylaniline, N-methylmorpholine,1,5-diazabicyclo[4.3.0]non-5-ene (DBN),1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane(DABCO), etc.

Such basic compounds can be used singly or in combinations of two ormore. More preferable basic compounds used in the reaction includeinorganic bases such as sodium hydride and potassium hydride.

A basic compound is usually used in an amount of 0.5 to 10 moles permole of Compound (1a), and preferably 0.5 to 6 moles per mole ofCompound (1a).

In Reaction Scheme 1, Compound (7) usually used in an amount of at leastabout 1 mole per mole of Compound (1a), and preferably about 1 to about5 moles per mole of Compound (1a).

The reaction can be conducted under normal pressure, under inert gasatmospheres including nitrogen, argon, etc., or under increasedpressure.

The reaction proceeds usually at 0° C. to 200° C., and preferably atroom temperature to 150° C., and is usually completed in about 1 toabout 30 hours.

The compound represented by General Formula (7), which is used as astarting material in Reaction Scheme 3 is an easily available knowncompound.

Compound (5) and Compound (2), which are the starting materials of thecompound of the invention, include novel compounds, and can be producedby various methods; for example, by methods according to the followingReaction Schemes 4 to 6.

wherein R₂, R₃, and R₈ are as defined above, and R₉ represents a loweralkoxy group.

The lower alkoxy group represented by R₉ in General Formula (9) has thesame definition as described above.

The compound represented by General Formula (5) can be produced by thereaction of the compound represented by General Formula (8) with thecompound represented by General Formula (9) in an inert solvent orwithout using any solvents, in the presence or absence of a basiccompound.

Examples of inert solvents include water; ether-based solvents such asdioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, diethyleneglycol dimethyl ether, and ethylene glycol dimethyl ether; aromatichydrocarbon-based solvents such as benzene, toluene, and xylene; loweralcohol-based solvents such as methanol, ethanol, and isopropanol;ketone-based solvents such as acetone and methyl ethyl ketone; and polarsolvents such as N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO),hexamethylphosphoric triamide, and acetonitrile. These inert solventscan be used singly or in combinations of two or more.

As a basic compound, various known inorganic bases and organic bases canbe used.

Inorganic bases include, for example, alkali metal hydroxides such assodium hydroxide, potassium hydroxide, cesium hydroxide, and lithiumhydroxide; alkali metal carbonates such as sodium carbonate, potassiumcarbonate, cesium carbonate, and lithium carbonate; alkali metalhydrogencarbonates such as lithium hydrogencarbonate, sodiumhydrogencarbonate, and potassium hydrogencarbonate; alkali metals suchas sodium and potassium; amides such as sodium amide; and inorganicbases of alkali metal hydrides such as sodium hydride and potassiumhydride.

Organic bases include, for example, alkali metal lower alkoxides such assodium methoxide, sodium ethoxide, sodium t-butoxide, potassiummethoxide, potassium ethoxide, and potassium t-butoxide; and amines suchas triethylamine, tripropylamine, pyridine, quinoline, piperidine,imidazole, N-ethyldiisopropylamine, dimethylaminopyridine,trimethylamine, dimethylaniline, N-methylmorpholine,1,5-diazabicyclo[4.3.0]non-5-ene (DBN),1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane(DABCO), etc.

Such basic compounds can be used singly or in combinations of two ormore. More preferable basic compounds used in the reaction includeinorganic bases such as sodium hydride and potassium hydride.

A basic compound is usually used in an amount of about 1 to about 10moles per mole of Compound (8), and preferably about 1 to about 6 molesper mole of Compound (8)

In Reaction Scheme 4, Compound (9) is usually used in an amount of atleast about 1 mole per mole of Compound (8), and preferably about 1 toabout 5 moles per mole of Compound (8).

The reaction can be conducted under normal pressure, under inert gasatmospheres including nitrogen, argon, etc., or under increasedpressure.

The reaction proceeds usually at room temperature to 200° C., andpreferably at room temperature to 150° C., and is usually completed inabout 1 to about 30 hours.

The compounds represented by General Formulae (8) and (9), which areused as starting materials in Reaction Scheme 4, are easily availableknown compounds.

wherein R₂, R₃, and R₈ are as defined above, and X₃ represents a halogenatom.

The halogen atom represented by X₃ in General Formula (9′) has the samedefinition as described above.

The compound represented by General Formula (5) can be produced by thereaction of the compound represented by General Formula (8′) with thecompound represented by General Formula (9′) in an inert solvent orwithout using any solvents, in the presence of a basic compound such ascesium carbonate and a copper catalyst such as copper iodide.

Examples of inert solvents include polar solvents such asN,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO),hexamethylphosphoric triamide, and acetonitrile. These inert solventscan be used singly or in combinations of two or more.

The reaction may be conducted in the presence of amino acids such asL-proline.

The reaction can be conducted under normal pressure, under inert gasatmospheres including nitrogen, argon, etc., or under increasedpressure.

The reaction proceeds usually at room temperature to 200° C., andpreferably at room temperature to 150° C., and is usually completed inabout 1 to about 30 hours.

The above reaction is specifically shown in Reference Example 58 below.

The compounds represented by General Formulae (8′) and (9′) used asstarting materials in Reaction Scheme 5 described above are knowncompounds, or can be produced easily using known compounds.

wherein R₄, R₅, R₆, and R₇ are as defined above, and X_(1a), representsa halogen atom. R₁₀ represents a lower alkyl group.

The lower alkyl group represented by R₁₀ and a halogen atom representedby X_(1a) have the same definitions as described above.

The compound represented by General Formula (12) can be produced by thecondensation reaction of the compounds represented by General Formulae(4), (10), and (11) in an inert solvent or without using any solvents.

Examples of inert solvents include water; ether-based solvents such asdioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, diethyleneglycol dimethyl ether, and ethylene glycol dimethyl ether; halogenatedhydrocarbon-based solvents such as methylene chloride, chloroform,1,2-dichloroethane, and carbon tetrachloride; aromatic hydrocarbon-basedsolvents such as benzene, toluene, and xylene; lower alcohol-basedsolvents such as methanol, ethanol, and isopropanol; and polar solventssuch as N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO),hexamethylphosphoric triamide, and acetonitrile. The compoundrepresented by General Formula (11) can be used as a solvent in place ofthe solvents mentioned above. These inert solvents can be used singly orin combinations of two or more.

In Reaction Scheme 6, Compound (10) is usually used in an amount of atleast 1 mole per mole of Compound (4), and preferably about 1 to about 5moles per mole of Compound (4).

An excess amount of Compound (11) is used relative to Compound (10).

The reaction can be conducted under normal pressure, under inert gasatmospheres including nitrogen, argon, etc., or under increasedpressure.

The reaction proceeds usually at room temperature to 200° C., andpreferably at room temperature to 150° C., and is usually completed inabout 1 to about 30 hours.

The compound represented by General Formula (13) can be produced by anannulation reaction of the compound represented by General Formula (12)in an inert solvent or without using any solvents.

Examples of inert solvents include ether-based solvents such as diphenylether.

The reaction can be conducted under normal pressure, under inert gasatmospheres including nitrogen, argon, etc., or under increasedpressure.

The reaction proceeds usually at room temperature to 300° C., andpreferably at 150 to 300° C., and is usually completed in about 1 toabout 30 hours.

The compound represented by General Formula (2a) can be produced by thereaction of the compound represented by General Formula (13) with thecompound represented by General Formula (14) in an inert solvent orwithout using any solvents, in the presence or absence of a basiccompound.

Examples of inert solvents include water; ether-based solvents such asdioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane,diethylene-glycol dimethyl ether, and ethylene glycol dimethyl ether;aromatic hydrocarbon-based solvents such as benzene, toluene, andxylene; lower alcohol-based solvents such as methanol, ethanol, andisopropanol; ketone-based solvents such as acetone and methyl ethylketone; polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), hexamethylphosphoric triamide, and acetonitrile. Theseinert solvents can be used singly or in combinations of two or more.

As a basic compound, various known inorganic bases and organic bases canbe used.

Inorganic bases include, for example, alkali metal hydroxides such assodium hydroxide, potassium hydroxide, cesium hydroxide, and lithiumhydroxide; alkali metal carbonates such as sodium carbonate, potassiumcarbonate, cesium carbonate, and lithium carbonate; alkali metalhydrogencarbonates such as lithium hydrogencarbonate, sodiumhydrogencarbonate, and potassium hydrogencarbonate; alkali metals suchas sodium and potassium; amides such as sodium amide; and alkali metalhydrides such as sodium hydride and potassium hydride

Organic bases include, for example, alkali metal alkoxide-based solventssuch as sodium methoxide, sodium ethoxide, sodium t-butoxide, potassiummethoxide, potassium ethoxide, and potassium t-butoxide; and amines suchas triethylamine, tripropylamine, pyridine, quinoline, piperidine,imidazole, N-ethyldiisopropylamine, dimethylaminopyridine,trimethylamine, dimethylaniline, N-methylmorpholine,1,5-diazabicyclo[4.3.0]non-5-ene (DBN),1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane(DABCO), etc.

Such basic compounds can be used singly or in combinations of two ormore. More preferable basic compounds used in the reaction includealkali metal carbonates such as sodium carbonate, potassium carbonate,cesium carbonate, and lithium carbonate, etc.

A basic compound is usually used in an amount of 0.5 to 10 moles permole of Compound (13), and preferably 0.5 to 6 moles per mole ofCompound (13).

In Reaction Scheme 6, Compound (14) is usually used in an amount of atleast 0.5 moles per mole of Compound (13), and preferably about 0.5 toabout 5 moles per mole of Compound (13).

The reaction can be conducted under normal pressure, under inert gasatmospheres including nitrogen, argon, etc., or under increasedpressure.

The reaction proceeds usually at room temperature to 200° C., andpreferably at room temperature to 150° C., and is usually completed inabout 1 to about 30 hours.

The compounds represented by General Formulae (10), (11) and (14), whichare used as starting materials in Reaction Scheme 6, are easilyavailable known compounds.

The raw material compounds used in each of the reaction schemesdescribed above may include suitable salts, and the objective compoundsobtained via each of the reactions may form suitable salts. Thesepreferable salts include the following preferable salts of Compound (1).

Suitable salts of Compound (1) are pharmacologically allowable salts,including metal salts such as alkali metal salts (e.g., sodium salts,potassium salts, and the like); alkaline earth metal salts (e.g.,calcium salts, magnesium salts, and the like); ammonium salts; salts ofinorganic bases such as alkali metal carbonates (e.g., lithiumcarbonate, potassium carbonate, sodium carbonate, cesium carbonate, andthe like); alkali metal hydrogencarbonates (e.g., lithiumhydrogencarbonate, sodium hydrogencarbonate, potassiumhydrogencarbonate, and the like); alkali metal hydroxides (e.g., lithiumhydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide,etc.); salts of organic bases such as tri(lower)alkylamine (e.g.,trimethylamine, triethylamine, N-ethyldiisopropylamine, and the like),pyridine, quinoline, piperidine, imidazole, picoline,dimethylaminopyridine, dimethylaniline, N-(lower)alkyl-morpholine (e.g.,N-methylmorpholine, etc.), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN),1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and1,4-diazabicyclo[2.2.2]octane (DABCO); inorganic acid salts such ashydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, andphosphate; and organic acid salts such as formate, acetate, propionate,oxalate, malonate, succinate, fumarate, maleate, lactate, malate,citrate, tartrate, carbonate, picrate, methanesulfonate,ethanesulfonate, p-toluenesulfonate, and glutamate.

In addition, compounds in the form in which solvate (for example,hydrate, ethanolate, etc.) was added to the starting materials andobjective compound shown in each of the reaction schemes are included ineach of the general formulae. Preferable solvates include hydrate.

Each of the objective compounds obtained according to the above reactionschemes can be isolated and purified from the reaction mixture by, forexample, after cooling the reaction mixture, performing an isolationprocedure such as filtration, concentration, extraction, etc., toseparate a crude reaction product, and then subjecting the crudereaction product to a usual purification procedure such as columnchromatography, recrystallization, etc.

The compound of Formula (1) according to the present invention naturallyincludes geometrical isomers, stereoisomers, optical isomers, and likeisomers.

The following points should be noted regarding the compound of GeneralFormula (1) shown above. When R₁ of General Formula (1) represents ahydrogen atom, the compound includes a tautomer of the quinolone ring.That is, when R₁ represents a hydrogen atom (1′) in the quinolonecompound of General Formula (1),

wherein R₂, R₃, R₄, R₅, R₆, and R₇ are as defined above, the compound ofthe tautomer can be represented by Formula (1″),

wherein R₂, R₃, R₄, R₅, R₆, and R₇ are as defined above.

That is, both of the compounds represented by Formulae (1′) and (1″) arein the tautomeric equilibrium state represented by the following balanceformula.

wherein R₂, R₃, R₄, R₅, R₆, and R₇ are as defined above.

Such tautomerism between a 4-quinolone compound and a 4-hydroxyquinolinecompound is technically known, and it is obvious for a person skilled inthe art that both of the above-described tautomers are balanced andmutually exchangeable.

Therefore, Compound (1) naturally includes the tautomers as mentionedabove.

In the specification, the constitutional formula of a 4-quinolonecompound is suitably used as a constitutional formula of the objectiveor starting material including compounds of such tautomers.

The compound of General Formula (1) and the salt thereof are used in theform of general pharmaceutical preparations. The preparations areobtained using typically employed diluents or excipients such asfillers, extenders, binders, wetting agents, disintegrators,surfactants, lubricants, etc. The form of such pharmaceuticalpreparations can be selected according to the purpose of the therapy.Typical examples include tablets, pills, powders, solutions,suspensions, emulsions, granules, capsules, suppositories, injections(solutions, suspensions, etc.) and the like.

To form tablets, any of various carriers conventionally known in thisfield can be used. Examples thereof include lactose, white sugar, sodiumchloride, glucose, urea, starch, calcium carbonate, kaolin, crystallinecellulose, silicic acid, and other excipients; water, ethanol, propanol,simple syrup, glucose solutions, starch solutions, gelatin solutions,carboxymethylcellulose, shellac, methylcellulose, potassium phosphate,polyvinylpyrrolidone and other binders; dry starch, sodium alginate,agar powder, laminarin powder, sodium hydrogen carbonate, calciumcarbonate, fatty acid esters of polyoxyethylene sorbitan, sodium laurylsulfate, stearic acid monoglycerides, starch, lactose and otherdisintegrators; white sugar, stearin, cacao butter, hydrogenated oilsand other disintegration inhibitors; quaternary ammonium bases, sodiumlauryl sulfate and other absorption promoters; glycerol, starch andother wetting agents; starch, lactose, kaolin, bentonite, colloidalsilicic acid and other adsorbents; purified talc, stearates, boric acidpowder, polyethylene glycol and other lubricants; etc. Further, suchtablets may be coated with typical coating materials as required, toprepare, for example, sugar-coated tablets, gelatin-coated tablets,enteric-coated tablets, film-coated tablets, double- or multi-layeredtablets, etc.

To form pills, any of various carriers conventionally known in thisfield can be used. Examples thereof include glucose, lactose, starch,cacao butter, hydrogenated vegetable oils, kaolin, talc and otherexcipients; gum arabic powder, tragacanth powder, gelatin, ethanol andother binders; laminarin, agar and other disintegrators; etc.

To form suppositories, any of various carriers conventionally known inthis field can be used. Examples thereof include polyethylene glycol,cacao butter, higher alcohols, esters of higher alcohols, gelatin, semisynthetic glycerides, etc.

Capsules can be prepared by mixing the active principal compound withthe above-mentioned carriers to enclose the former in a hard gelatincapsule, soft gelatin capsule or the like.

To form an injection, a solution, emulsion or suspension is sterilizedand preferably made isotonic to blood. Any of the diluents widely usedfor such forms in this field can be employed to form the injection.Examples of such diluents include water, ethyl alcohol, macrogol,propylene glycol, ethoxylated isostearyl alcohol, polyoxylatedisostearyl alcohol, fatty acid esters of polyoxyethylene sorbitan, etc.

In this case, the pharmaceutical preparation may contain sodiumchloride, glucose or glycerol in an amount sufficient to prepare anisotonic solution, and may contain typical solubilizers, buffers,analgesic agents, etc. Further, if necessary, the pharmaceuticalpreparation may contain coloring agents, preservatives, flavors,sweetening agents, etc., and/or other medicines.

The amount of the compound represented by the General Formula (1) andthe salt thereof included in the pharmaceutical preparation of thepresent invention is not limited, and can be suitably selected from awide range. The proportion is generally about 0.1 to about 70 wt. %,preferably about 0.1 to about 30 wt. % of the pharmaceuticalpreparation.

The route of administration of the pharmaceutical preparation of thepresent invention is not particularly limited, and the preparation isadministered by a route suitable to the form of the preparation,patient's age, sex and other conditions, and the status of the disease.For example, tablets, pills, solutions, suspensions, emulsions, granulesand capsules are administered orally. Injections are intravenouslyadministered singly or as mixed with typical injection transfusions suchas glucose solutions, amino acid solutions or the like, or singlyadministered intramuscularly, intracutaneously, subcutaneously orintraperitoneally, as required. Suppositories are administeredintrarectally.

The dosage of the pharmaceutical preparation of the invention issuitably selected according to the method of use, patient's age, sex andother conditions, and severity of the disease. The amount of activeprincipal compound is usually about 0.1 to about 10 mg/kg bodyweight/day. Further, it is desirable that the pharmaceutical preparationin each unit of the administration form contains the active principalcompound in an amount of about 1 to about 200 mg.

The use of the compound of the present invention in combination withL-dopa preparations, dopamine receptor agonists, dopamine metabolismenzyme inhibitors, dopamine release-rate-promoting preparations, centralanticholinergic agents, and the like can achieve effects such as dosagereduction, improvement of side effects, increased therapeutic efficacy,etc., which were not attained by known therapies.

EFFECT OF THE INVENTION

The compound of the present invention has protecting and improvingmitochondrial functional activity and protecting and repairing neuronactivity, etc., and thus is effective in the treatment and prevention ofneurodegenerative diseases, diseases relating to neurodegenerativedisorder, and diseases relating to mitochondrial dysfunction.

Neurodegenerative diseases include Parkinson's disease, Parkinson'ssyndrome, juvenile parkinsonism, striatonigral degeneration, progressivesupranuclear palsy, pure akinesia, Alzheimer's disease, Pick's disease,prion disease, corticobasal degeneration, diffuse Lewy body disease,Huntington's disease, chorea-acanthocytosis, benign hereditary chorea,paroxysmal choreoathetosis, essential tremor, essential myoclonus,Gilles de la Tourette's syndrome, Rett's syndrome, degenerative ballism,dystonia musculorum deformance, athetosis, spasmodic torticollis, Meigesyndrome, cerebral palsy, Wilson's disease, Segawa's disease,Hallervorden-Spatz syndrome, neuroaxonal dystrophy, pallidal atrophy,spino-cerebellar degeneration, cerebral cortical atrophy, Holmes-typecerebellar atrophy, olivopontocerebellar atrophy, hereditaryolivopontocerebellar atrophy, Joseph disease, dentatorubropallidoluysianatrophy, Gerstmann-Straussler-Scheinker disease, Friedreich's Ataxia,Roussy-Levy syndrome, May-White syndrome, congenital cerebellar ataxia,hereditary episodic ataxia, ataxia telangiectasia, amyotrophic lateralsclerosis, progressive bulbar palsy, spinal progressive muscularatrophy, spinobulbar muscular atrophy, Werdnig-Hoffmann disease,Kugelberg-Welander disease, hereditary spastic paraparesis,syringomyelia, syringobulbia, Arnold-Chiari malformation, Stiffmansyndrome, Klippel-Feil syndrome, Fazio-Londe syndrome, lower myelopathy,Dandy-Walker syndrome, spina bifida, Sjogren-Larsson syndrome, radiationmyelopathy, age-related macular degeneration and cerebral apoplexy(e.g., cerebral infarction, cerebral hemorrhage, etc.).

Diseases induced by neurological dysfunction include spinal cord injury,chemotherapy-induced neuropathy, diabetic neuropathy, radiation damageand demyelinating diseases (e.g., multiple sclerosis, acute disseminatedencephalomyelitis, transverse myelitis, progressive multifocalleucoencephalopathy, subacute sclerosing panencephalitis, chronicinflammatory demyelinating polyneuropathy, Guillain-Barre syndrome,etc.)

Diseases induced by deterioration of mitochondrion function includePearson's syndrome, diabetes, deafness, malignant migraine, Leber'sdisease, MELAS, MERRF, MERRF/MELAS overlap syndrome, NARP, puremyopathy, mitochondrial cardiomyopathy, myopathy, dementia,gastrointestinal ataxia, acquired sideroblastic anemia,aminoglycoside-induced hearing loss, complex III deficiency due toinherited variants of cytochrome b, multiple symmetrical lipomatosis,ataxia, myoclonus, retinopathy, MNGIE, ANTI disease, Twinkle disease,POLG disease, recurrent myoglobinuria, SANDO, ARCO, complex Ideficiency, complex II deficiency, optic nerve atrophy, fatal infantilecomplex IV deficiency, mitochondrial DNA deficiency, mitochondrial DNAdeficiency syndrome, Leigh's encephalomyelopathy,chronic-progressive-external-ophthalmoplegia syndrome (CPEO),Kearns-Sayre syndrome, encephalopathy, lactacidemia, myoglobinuria,drug-induced mitochondrial diseases, schizophrenia, major depressiondisorder, bipolar I disorder, bipolar II disorder, mixed episode,dysthymic disorders, atypical depression, seasonal affective disorders,postpartum depression, minor depression, recurrent brief depressivedisorder, intractable depression/chronic depression, double depression,acute renal failure.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention is described in more detail withreference to Reference Examples, Examples and Pharmacological TestExamples.

REFERENCE EXAMPLE 1 N-Cyclohexyl-4-fluoro-2-nitro-N-methylaniline

Potassium carbonate (6.0 g, 43.5 mmol) and N-methylcyclohexylamine (4.6g, 40.6 mmol) were added to a N-methylpyrolidone (NMP) solution (20 ml)of 2,5-difluoronitrobenzene (5.0 g, 31.4 mmol), and stirred at 100° C.for 3 hours. The reaction mixture was cooled to room temperature, waterwas added, and the resulting mixture was extracted with ethyl acetate.The organic layer was washed with water, and then dried over anhydrousmagnesium sulfate. The resulting dry product was concentrated underreduced pressure to thereby obtain 7.0 g of oily yellowN-cyclohexyl-4-fluoro-2-nitro-N-methylaniline (yield: 89%).

¹H-NMR (CDCl₃) δppm:

1.12-1.80 (10H, m), 2.67 (3H, s), 3.00-3.09 (1H, m), 7.07-7.20 (2H, m),7.42-7.47 (1H, m).

The compounds of the following Reference Examples 2 to 5 were preparedin the same manner as in the above Reference Example 1, usingcorresponding starting materials.

REFERENCE EXAMPLE 2 4-Fluoro-N-(2-methoxyethyl)-N-methyl-2-nitroaniline

¹H-NMR (CDCl₃) δppm:

2.85 (3H, s), 3.25-3.31 (5H, m), 3.52 (2H, t, J=5.6 Hz), 7.16-7.20 (2H,m), 7.43-7.47 (1H, m).

REFERENCE EXAMPLE 3 4-Fluoro-N-isobutyl-N-methyl-2-nitroaniline

¹H-NMR (CDCl₃) δppm:

0.89 (3H, s), 0.91 (3H, s), 1.89-1.98 (1H, m), 2.81 (3H, s), 2.92 (2H,d, J=7.5 Hz), 7.15-7.20 (2H, m), 7.42-7.46 (1H, m).

REFERENCE EXAMPLE 4 4-Fluoro-N-isopropyl-N-methyl-2-nitroaniline

¹H-NMR (CDCl₃) δppm:

1.16 (3H, s), 1.19 (3H, s), 2.67 (3H, s), 3.50-3.61 (1H, m), 7.15-7.20(2H, m), 7.43-7.46 (1H, m).

REFERENCE EXAMPLE 5 4-Fluoro-N-methyl-2-nitro-N-propylaniline

¹H-NMR (CDCl₃) δppm:

0.84 (3H, t, J=7.5 Hz), 1.51-1.66 (2H, m), 2.77 (3H, s), 3.00 (2H, t,J=7.5 Hz), 7.05-7.20 (2H, m), 7.44 (1H, dd, J=2.75 Hz, J=8.0 Hz)

REFERENCE EXAMPLE 6 4-Fluoro-2-nitro-1-propylsulfanylbenzene

Potassium carbonate (5.0 g, 36.2 mmol) and 1-propanethiol (2.7 g, 35.5mmol) were added to a N-methylpyrolidone (NMP) solution (15 ml) of2,5-difluoronitrobenzene (5.0 g, 31.4 mmol), and the mixture obtainedwas stirred at 90° C. for 2 hours. After the reaction mixture was cooledto room temperature, water (50 ml) was added, and the reaction productwas extracted with ethyl acetate (100 ml). The organic layer was washedwith water, and then dried over anhydrous magnesium sulfate. Theresulting dry product was concentrated under reduced pressure to therebyobtain 6.7 g of powdery yellow 4-fluoro-2-nitro-1-propylsulfanylbenzene(yield: 99%).

¹H-NMR (CDCl₃) δppm:

1.06 (3H, t, J=7.5 Hz), 1.68-1.83 (2H, m), 2.89 (2H, t, 7.5 Hz),7.27-7.42 (2H, m), 7.89 (2H, dd, J=2.75 Hz, J=8.5 Hz).

REFERENCE EXAMPLE 7 1-tert-Butoxy-4-fluoro-2-nitrobenzene

A tetrahydrofuran (THF) solution (20 ml) of potassium tert-butoxide(3.55 g, 31.6 mmol) was cooled in an methanol-ice bath, and 4.2 g of2,5-difluoronitrobenzene (26.4 mmol) was further added. The mixture washeated to room temperature, stirred for 96 hours, and further stirred at60° C. for 1 hour. Water (2 ml) and 2N-hydrochloric acid (2 ml) wereadded to the reaction mixture while cooling with an ice water bath, andsubsequently water was added. The resulting mixture was extracted withethyl acetate. The organic layer was concentrated under reducedpressure, and the residue was then purified using silica gel columnchromatography (n-hexane:ethyl acetate=19:1). The purified product wasconcentrated under reduced pressure to thereby obtain 4.5 g of oilyorange 1-tert-butoxy-4-fluoro-2-nitrobenzene (yield: 80%).

¹H-NMR (CDCl₃) δppm:

1.38 (9H, s), 7.18-7.20 (2H, m), 7.47 (1H, d, J=7.1 Hz).

REFERENCE EXAMPLE 8 4-Fluoro-2-nitro-1-propoxybenzene

A N,N-dimethylformamide (DMF) solution (3 ml) of potassium carbonate(3.48 g, 25.2 mmol) and 1-iodopropane (3.95 g, 23.2 mmol) was added to aDMF solution (7 ml) of 4-fluoro-2-nitrophenol (3.3 g, 21.0 mmol). Themixture was stirred at room temperature for 48 hours. Water was added tothe reaction mixture, and the resulting mixture was extracted with ethylacetate. The organic layer was washed with a saturated sodium chloridesolution twice, and concentrated under reduced pressure. The residue waspurified using silica gel column chromatography (n-hexane:ethylacetate=9:1). The purified product was concentrated under reducedpressure to thereby obtain 4.03 g of oily yellow4-fluoro-2-nitro-1-propoxybenzene (yield: 96%).

¹H-NMR (CDCl₃) δppm:

1.06 (3H, t, J=7.4 Hz), 1.78-1.92 (2H, m), 4.04 (2H, t, J=6.4 Hz), 7.04(1H, dd, J=4.3 Hz, J=9.2 Hz), 7.21-7.29 (1H, m), 7.58 (1H, dd, J=3.1 Hz,J=7.8 Hz).

The compounds of the following Reference Examples 9 to 16 were preparedin the same manner as the above Reference Examples 7 to 8, usingcorresponding starting materials.

REFERENCE EXAMPLE 9 4-Fluoro-1-isopropoxy-2-nitrobenzene

¹H-NMR (CDCl₃) δppm:

1.36 (3H, s), 4.54-4.63 (1H, m), 7.02-7.05 (1H, m), 7.18-7.26 (1H, m),7.49 (1H, dd, J=3.0 Hz, J=7.5 Hz).

REFERENCE EXAMPLE 10 1-Ethoxy-4-fluoro-2-nitrobenzene

¹H-NMR (CDCl₃) δppm:

1.44 (3H, t, J=7.0 Hz), 4.08 (2H, q, J=7.0 Hz), 7.02 (1H, dd, J=4.25 Hz,J=9.25 Hz), 7.22-7.30 (1H, m), 7.56 (1H, dd, J=3.25 Hz, J=7.75 Hz).

REFERENCE EXAMPLE 11 1-Cyclopropylmethoxy-4-fluoro-2-nitrobenzene

¹H-NMR (CDCl₃) δppm:

0.36-0.41 (2H, m), 0.61-0.69 (2H, m), 1.22-1.28 (1H, m), 3.95 (2H, d,J=6.8 Hz), 7.04 (1H, dd, J=4.4 Hz, J=9.2 Hz), 7.20-7.27 (1H, m), 7.57(1H, dd, J=3.1 Hz, J=7.8 Hz).

REFERENCE EXAMPLE 12 4-Fluoro-2-nitro-1-(4,4,4-trifluorobutoxy)benzene

¹H-NMR (CDCl₃) δppm:

2.04-2.16 (2H, m), 2.31-2.44 (2H, m), 4.14 (2H, t, J=5.9 Hz), 7.04 (1H,dd, J=4.3 Hz, J=9.2 Hz), 7.24-7.32 (1H, m), 7.61 (1H, dd, J=3.2 Hz,J=7.8 Hz).

REFERENCE EXAMPLE 13 4-Fluoro-1-(2-methoxyethoxy)-2-nitrobenzene

¹H-NMR (CDCl₃) δppm:

3.45 (3H, s), 3.78 (2H, t, J=4.8 Hz), 4.24 (2H, t, J=4.8 Hz), 7.12 (1H,dd, J=4.4 Hz, J=9.2 Hz), 7.23-7.30 (1H, m), 7.59 (1H, dd, J=3.1 Hz,J=7.8 Hz).

REFERENCE EXAMPLE 14 1-Cyclopentyloxy-4-fluoro-2-nitrobenzene

¹H-NMR (CDCl₃) δppm:

1.62-1.66 (2H, m), 1.83-1.94 (6H, m), 4.82-4.86 (1H, m), 7.04 (1H, dd,J=4.4 Hz, J=9.3 Hz), 7.19-7.27 (1H, m), 7.54 (1H, dd, J=3.2 Hz, J=7.8Hz).

REFERENCE EXAMPLE 15 1-Cyclobutylmethoxy-4-fluoro-2-nitrobenzene

¹H-NMR (CDCl₃) δppm:

1.90-2.02 (4H, m), 2.08-2.15 (2H, m), 2.77-2.81 (1H, m), 4.03 (2H, d,J=6.2 Hz), 7.04 (1H, dd, J=4.3 Hz, J=9.2 Hz), 7.21-7.28 (1H, m), 7.58(1H, dd, J=3.1 Hz, J=7.8 Hz).

REFERENCE EXAMPLE 16 2-(4-Fluoro-2-nitrophenoxymethyl)tetrahydrofuran

¹H-NMR (CDCl₃) δppm:

1.88-2.12 (4H, m), 3.80-3.94 (2H, m), 4.11 (2H, d, J=4.0 Hz), 4.27-4.32(1H, m), 7.10 (1H, dd, J=4.4 Hz, J=9.3 Hz), 7.22-7.30 (1H, m), 7.59 (1H,dd, J=3.1 Hz, J=7.8 Hz).

REFERENCE EXAMPLE 172-[3-(4-Fluoro-2-nitrophenoxy)propyl]isoindole-1,3-dione

Potassium carbonate (10.8 g, 78.1 mmol) and N-(3-bromopropyl)phthalimide(12.1 g, 45.1 mmol) were added to a N,N-dimethylformamide (DMF) solution(80 ml) of 4-fluoro-2-nitrophenol (6.0 g, 38.2 mmol), and the mixturewas stirred at 60° C. for 4 hours. After the reaction mixture was cooledto room temperature, water (200 ml) was added, and the reaction mixturewas then cooled with ice. The precipitated insoluble matter wascollected by filtration. After being washed with water (50 ml×3), thesubstance remaining in the filter was air-dried, giving 13.2 g ofpowdery pale yellow2-[3-(4-fluoro-2-nitrophenoxy)propyl]isoindole-1,3-dione (yield: 100%).

¹H-NMR (CDCl₃) δppm:

2.18-2.28 (2H, m), 3.93 (2H, t, J=6.5 Hz), 4.15 (2H, t, J=6.0 Hz), 7.04(1H, dd, J=4.3 Hz, J=9.2 Hz), 7.23-7.28 (1H, m), 7.58 (1H, dd, J=3.1 Hz,J=7.8 Hz), 7.69-7.74 (2H, m), 7.81-7.85 (2H, m).

REFERENCE EXAMPLE 18 3-(4-Fluoro-2-nitrophenoxy)propylamine

6.5 g of 2-[3-(4-fluoro-2-nitrophenoxy)propyl]isoindole-1,3-dione wassuspended in ethanol (140 ml), and hydrazine hydrate (3.0 ml) was addedto the resulting suspension. The mixture was stirred for 3.5 hours whileheating under reflux. The reaction mixture was cooled to roomtemperature, and concentrated under reduced pressure. 13 ml of 5N sodiumhydroxide aqueous solution was added to the residue, and the resultingmixture was extracted with dichloromethane. The organic layer was washedwith a saturated sodium chloride solution, and then dried over anhydrousmagnesium sulfate. The resulting dry product was concentrated underreduced pressure to thereby obtain 4.03 g of oily red orange3-(4-fluoro-2-nitrophenoxy)propylamine (yield: 100%).

¹H-NMR (CDCl₃) δppm:

1.92-2.02 (2H, m), 2.94 (2H, t, J=6.5 Hz), 4.19 (2H, t, J=5.9 Hz), 7.07(1H, dd, J=4.3 Hz, J=9.2 Hz), 7.22-7.30 (1H, m), 7.59 (1H, dd, J=3.1 Hz,J=7.8 Hz).

REFERENCE EXAMPLE 19 N-[3-(4-Fluoro-2-nitrophenoxy)propyl]acetamide

Pyridine (1.5 ml, 18.6 mmol) and acetic anhydride (0.97 g, 10.3 mmol)were added to a dichloromethane solution of3-(4-fluoro-2-nitrophenoxy)propylamine (2.0 g, 9.33 mmol), while beingcooled with ice, and then dichloromethane (4 ml) was further added. Theresulting mixture was stirred at room temperature for 15 hours.2N-hydrochloric acid (9.5 ml) was added to the reaction mixture, and themixture was stirred. Water was added to the mixture, and the resultingmixture was extracted with dichloromethane. After being washed with asaturated sodium chloride aqueous solution, the organic layer wasconcentrated under reduced pressure. The residue was then purified bysilica gel column chromatography (dichloromethane:methanol=30:1→20:1).The purified product was concentrated under reduced pressure to therebyobtain 2.13 g of oily yellowN-[3-(4-fluoro-2-nitrophenoxy)propyl]acetamide (yield: 89%).

¹H-NMR (CDCl₃) δppm:

2.04 (3H, s), 2.03-2.12 (2H, m), 3.48-3.55 (2H, m), 4.20 (2H, t, J=5.5Hz), 6.56 (1H, brs), 7.08 (1H, dd, J=4.3 Hz, J=9.3 Hz), 7.26-7.36 (1H,m), 7.70 (1H, dd, J=3.2 Hz, J=7.8 Hz).

REFERENCE EXAMPLE 20N-[3-(4-Fluoro-2-nitrophenoxy)propyl]methanesulfonamide

Pyridine (1.5 ml, 18.6 mmol) and methanesulfonyl chloride (0.8 ml, 10.3mmol) were added, while being cooled with ice, to a dichloromethanesolution of 3-(4-fluoro-2-nitrophenoxy)propylamine (2.0 g, 9.33 mmol),and dichloromethane (4 ml) was further added. The resulting mixture wasstirred at room temperature for 24 hours, and methanesulfonyl chloride(0.12 ml, 1.5 mmol) was further added thereto, and then the mixture wasstirred at room temperature for 15 hours. 2N hydrochloric acid (9.5 ml)was added to the reaction mixture, and the mixture was stirred. Waterwas added to the mixture, and the resulting mixture was extracted withdichloromethane. After being washed with a saturated sodium chlorideaqueous solution, the organic layer was concentrated under reducedpressure, and the residue was then purified by silica gel columnchromatography (n-hexane:ethyl acetate=4:1→1:1). The purified productwas concentrated under reduced pressure to thereby obtain 1.2 g of oilyyellow orange N-[3-(4-fluoro-2-nitrophenoxy)propyl]methansulfonamide(yield: 44%).

¹H-NMR (CDCl₃) δppm:

2.09-2.18 (2H, m), 3.00 (3H, s), 3.39-3.46 (2H, m), 4.23 (2H, t, J=5.6Hz), 5.00 (1H, brs), 7.09 (1H, dd, J=4.3 Hz, J=9.2 Hz), 7.26-7.35 (1H,m), 7.66 (1H, dd, J=3.1 Hz, J=7.8 Hz).

REFERENCE EXAMPLE 21 Phenyl[3-(4-Fluoro-2-nitrophenoxy)propyl]carbamate

Triethylamine (2.90 ml, 21.4 mmol) and phenyl chlorocarbonate (2.52 ml,20.0 mmol) were added to a dioxane solution (43 ml) of3-(4-fluoro-2-nitrophenoxy)propylamine (4.03 g, 18.8 mmol), while beingcooled with ice, and the mixture was stirred at room temperature for 0.5hours. The reaction mixture was concentrated under reduced pressure, andthe residue was then purified by silica gel column chromatography(dichloromethane:ethyl acetate=30:1). The purified product wasconcentrated to dryness under reduced pressure to thereby obtain 5.92 gof powdery yellow phenyl[3-(4-fluoro-2-nitrophenoxy)propyl]carbamate(yield: 94%).

¹H-NMR (CDCl₃) δppm:

2.09-2.18 (2H, m), 3.48-3.56 (2H, m), 4.21 (2H, t, J=5.7 Hz), 5.69 (1H,brs), 7.05-7.20 (4H, m), 7.26-7.37 (3H, m), 7.65 (1H, dd, J=3.1 Hz,J=7.8 Hz).

REFERENCE EXAMPLE 22 3-[3-(4-Fluoro-2-nitrophenoxy)propyl]-1,1-dimethylurea

A 50% dimethylamine aqueous solution (2.5 ml) was added to a DMFsolution (25 ml) of phenyl[3-(4-fluoro-2-nitrophenoxy)propyl]carbamate(5.89 g, 17.6 mmol), and the mixture was stirred at room temperature for24 hours. Water was added to the reaction mixture, and the resultingmixture was extracted with ethyl acetate. The organic layer was washedwith a saturated sodium chloride aqueous solution twice, andconcentrated under reduced pressure. The residue was then purified bysilica gel column chromatography (dichloromethane: ethylacetate=19:1→4:1→2:1). The purified product was concentrated to drynessunder reduced pressure to thereby obtain 4.10 g of oily pale yellow3-[3-(4-fluoro-2-nitrophenoxy)propyl]-1,1-dimethyl urea (yield: 82%).

¹H-NMR (CDCl₃) δppm:

2.03-2.12 (2H, m), 2.89 (6H, s), 3.42-3.49 (2H, m), 4.17 (2H, t, J=5.8Hz), 4.85 (1H, brs), 7.09 (1H, dd, J=4.3 Hz, J=9.3 Hz), 7.24-7.32 (1H,m), 7.61 (1H, dd, J=3.2 Hz, J=7.8 Hz).

REFERENCE EXAMPLE 231-[3-(4-Fluoro-2-nitrophenoxy)propyl]-1,3,3-trimethylurea

Sodium hydride (55% in oil) (396 mg, 9.1 mmol) was added, while beingcooled with ice, to a DMF solution (9 ml) of 2.0 g of3-[3-(4-fluoro-2-nitrophenoxy)propyl]-1,1-dimethyl urea (7.0 mmol) andthe mixture was stirred at room temperature for 5 minutes. Methyl iodide(0.735 ml, 11.8 mmol) was added to the mixture and the resulting mixturewas stirred at room temperature for 48 hours. Water was added to thereaction mixture and extraction with ethyl acetate was performed. Afterbeing washed with a saturated sodium chloride aqueous solution, theorganic layer was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (dichloromethane:ethylacetate=9:1→6:1). The purified product was concentrated under reducedpressure to thereby obtain 0.83 g of oily pale yellow1-[3-(4-fluoro-2-nitrophenoxy)propyl]-1,3,3-trimethylurea (yield: 40%).

¹H-NMR (CDCl₃) δppm:

2.04-2.14 (2H, m), 2.76 (6H, s), 2.83 (3H, s), 3.38 (2H, t, J=6.9 Hz),4.09 (2H, t, J=5.9 Hz), 7.04 (1H, dd, J=4.3 Hz, J=9.3 Hz), 7.22-7.30(1H, m), 7.60 (1H, dd, J=3.1 Hz, J=7.7 Hz).

REFERENCE EXAMPLE 24 5-Fluoro-2-propoxyaniline

4-Fluoro-2-nitro-1-propoxybenzene (2.0 g, 10.0 mmol) and 5% palladiumcarbon (750 mg) were added to ethanol (30 ml). Catalytic reduction wasconducted at room temperature and atmospheric pressure (normalpressure). The catalyst was removed by celite filtration, and thefiltrate was concentrated under reduced pressure. The residue wasdissolved in dichloromethane, and dried over anhydrous magnesiumsulfate. The resulting dry product was concentrated under reducedpressure to thereby obtain 1.45 g of oily red orange5-fluoro-2-propoxyaniline (yield: 86%).

¹H-NMR (CDCl₃) δppm:

1.04 (3H, t, J=7.4 Hz), 1.74-1.88 (2H, m), 3.89 (2H, brs), 3.90 (2H, t,J=6.5 Hz), 6.31-6.46 (2H, m), 6.66 (1H, dd, J=5.1 Hz, J=8.7 Hz).

The compounds of the following Reference Examples 25 to were prepared inthe same manner as the above Reference Example 24, using correspondingstarting materials.

REFERENCE EXAMPLE 25 5-Fluoro-2-isopropoxyaniline

¹H-NMR (CDCl₃) δppm:

1.32 (3H, s), 1.35 (3H, s), 3.88 (2H, brs), 4.38-4.48 (1H, m), 6.31-6.46(2H, m), 6.68-6.73 (1H, m).

REFERENCE EXAMPLE 26 2-Ethoxy-5-fluoroaniline

¹H-NMR (CDCl₃) δppm:

1.39 (3H, t, J=7.0 Hz), 3.90 (2H, brs), 3.97 (2H, q, J=7.0 Hz),6.31-6.46 (2H, m), 6.63-6.68 (1H, m).

REFERENCE EXAMPLE 27 5-Fluoro-2-morpholin-4-ylaniline

¹H-NMR (CDCl₃) δppm:

2.83 (4H, t, J=4.6 Hz), 3.81 (4H, t, J=4.6 Hz), 4.13 (2H, brs),6.38-6.45 (2H, m), 6.93-6.97 (1H, m).

REFERENCE EXAMPLE 28 5-Fluoro-2-pyrrolidin-1-ylaniline

¹H-NMR (CDCl₃) δppm:

1.88-1.94 (4H, m), 2.94-3.00 (4H, m), 4.03 (2H, brs), 6.35-6.46 (2H, m),6.90-6.95 (1H, m).

REFERENCE EXAMPLE 29 2-Cyclopropylmethoxy-5-fluoroaniline

¹H-NMR (CDCl₃) δppm:

0.29-0.35 (2H, m), 0.58-0.65 (2H, m), 1.22-1.29 (1H, m), 3.77 (2H, d,J=6.9 Hz), 3.94 (2H, brs), 6.29-6.46 (2H, m), 6.64 (1H, dd, J=5.1 Hz,J=8.8 Hz).

REFERENCE EXAMPLE 30 N¹-Cyclohexyl-4-fluoro-N¹-methylbenzene-1,2-diamine

¹H-NMR (CDCl₃) δppm:

1.11-1.31 (4H, m), 1.55-1.82 (6H, m), 2.57-2.68 (4H, m), 4.18 (2H, brs),6.33-6.44 (2H, m), 6.92-6.98 (1H, m).

REFERENCE EXAMPLE 314-Fluoro-N¹-(2-methoxyethyl)-N¹-methylbenzene-1,2-diamine

¹H-NMR (CDCl₃) δppm:

2.70 (3H, s), 2.96 (2H, t, J=5.4 Hz), 3.39 (3H, s), 3.45 (2H, t, J=5.4Hz), 4.38 (2H, brs), 6.33-6.43 (2H, m), 6.93-6.99 (1H, m).

REFERENCE EXAMPLE 32 4-Fluoro-N¹-isobutyl-N¹-methylbenzene-1,2-diamine

¹H-NMR (CDCl₃) δppm:

0.92 (3H, s), 0.94 (3H, s), 1.62-1.83 (1H, m), 2.54-2.60 (5H, m),6.30-6.49 (2H, m), 6.82-6.93 (1H, m).

REFERENCE EXAMPLE 33 4-Fluoro-N¹-isopropyl-N¹-methylbenzene-1,2-diamine

¹H-NMR (CDCl₃) δppm:

1.05 (3H, s), 1.07 (3H, s), 2.55 (3H, s), 3.06-3.17 (1H, m), 4.16 (2H,brs), 6.34-6.45 (2H, m), 6.91-6.97 (1H, m).

REFERENCE EXAMPLE 34 4-Fluoro-N¹-methyl-N¹-propylbenzene-1,2-diamine

¹H-NMR (CDCl₃) δppm: 0.86 (3H, t, J=7.4 Hz), 1.41-1.56 (2H, m), 2.57(3H, s), 2.72 (2H, t, J=7.25 Hz), 4.18 (2H, brs), 6.35-6.44 (2H, m),6.91-6.97 (1H, m).

REFERENCE EXAMPLE 35 N-[3-(2-Amino-4-fluorophenoxy)propyl]acetamide

¹H-NMR (CDCl₃) δppm:

1.95-2.05 (2H, m), 1.97 (3H, s), 3.42-3.50 (2H, m), 3.92 (2H, brs), 4.02(2H, t, J=5.9 Hz), 5.83 (1H, brs), 6.32-6.47 (2H, m), 6.68 (1H, dd,J=5.0 Hz, J=8.8 Hz).

REFERENCE EXAMPLE 36N-[3-(2-Amino-4-fluorophenoxy)propyl]methanesulfonamide

¹H-NMR (CDCl₃) δppm:

2.02-2.11 (2H, m), 2.94 (3H, s), 3.33-3.40 (2H, m), 3.91 (2H, brs), 4.07(2H, t, J=5.7 Hz), 4.76 (1H, brs), 6.32-6.46 (2H, m), 6.68 (1H, dd,J=5.0 Hz, J=8.8 Hz).

REFERENCE EXAMPLE 37 5-Fluoro-2-(4,4,4-trifluorobutoxy)aniline

¹H-NMR (CDCl₃) δppm:

2.01-2.12 (2H, m), 2.22-2.41 (2H, m), 3.87 (2H, brs), 4.01 (2H, t, J=6.0Hz), 6.32-6.47 (2H, m), 6.65 (1H, dd, J=5.0 Hz, J=8.8 Hz).

REFERENCE EXAMPLE 381-[3-(2-Amino-4-fluorophenoxy)propyl]-1,3,3-trimethylurea

¹H-NMR (CDCl₃) δppm:

1.99-2.10 (2H, m), 2.78 (6H, s), 2.84 (3H, s), 3.37 (2H, t, J=6.9 Hz),3.94 (2H, brs), 3.97 (2H, t, J=6.1 Hz), 6.30-6.45 (2H, m), 6.65 (1H, dd,J=5.1 Hz, J=8.8 Hz).

REFERENCE EXAMPLE 39 5-Fluoro-2-(2-methoxyethoxy)aniline

¹H-NMR (CDCl₃) δppm:

3.43 (3H, s), 3.70-3.73 (2H, m), 3.99 (2H, brs), 4.07-4.10 (2H, m),6.30-6.45 (2H, m), 6.72 (1H, dd, J=5.1 Hz, J=8.7 Hz).

REFERENCE EXAMPLE 40 2-Cyclopentyloxy-5-fluoroaniline

¹H-NMR (CDCl₃) δppm:

1.56-1.66 (2H, m), 1.75-1.87 (6H, m), 3.85 (2H, brs), 4.69-4.72 (1H, m),6.30-6.45 (2H, m), 6.66 (1H, dd, J=5.1 Hz, J=8.8 Hz).

REFERENCE EXAMPLE 41 2-Cyclobutylmethoxy-5-fluoroaniline

¹H-NMR (CDCl₃) δppm:

1.86-1.96 (4H, m), 2.08-2.16 (2H, m), 2.74-2.80 (1H, m), 3.90 (2H, brs),3.91 (2H, d, J=6.7 Hz), 6.31-6.45 (2H, m), 6.66 (1H, dd, J=5.1 Hz, J=8.8Hz).

REFERENCE EXAMPLE 42 2-tert-Butoxy-5-fluoroaniline

¹H-NMR (CDCl₃) δppm:

1.37 (9H, s), 3.87 (2H, brs), 6.27-6.45 (2H, m), 6.85 (1H, dd, J=5.6 Hz,J=8.8 Hz).

REFERENCE EXAMPLE 43 5-Fluoro-2-propylsulfanylaniline

4-Fluoro-2-nitro-1-propylsulfanylbenzene (6.7 g, 31.1 mmol) wasdissolved in a mixed solvent of ethanol (40 ml) and water (4 ml).Ammonium chloride (17 g, 0.32 mol) was added to the resulting mixture,and zinc powder (20 g, 0.31 mol) were added little by little. Theresulting mixture was then stirred at room temperature for 1 hour.Insoluble matter was removed by filtration, and the filtrate wasconcentrated under reduced pressure to thereby obtain 5.8 g of oilybrown 5-fluoro-2-propylsulfanylaniline (yield: 93%).

¹H-NMR (CDCl₃) δppm:

0.96 (3H, t, J=7.3 Hz), 1.49-1.64 (2H, m), 2.62 (2H, t, J=7.4 Hz), 4.51(2H, brs), 6.35-6.47 (2H, m), 7.32-7.38 (1H, m).

REFERENCE EXAMPLE 44 4,5-Difluoro-2-propoxyaniline

A toluene solution (20 ml) of benzophenone imine (2.38 g, 13.1 mmol),tris(dibenzylidene acetone)dipalladium (275 mg, 0.3 mmol),9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (XANTPHOS) (347 mg, 0.6mmol) and cesium carbonate (5.83 g, 17.9 mmol) were added to a toluenesolution (60 ml) of 1-bromo-4,5-difluoro-2-propoxybenzene (3.0 g, 11.9mmol). The mixture was stirred under a nitrogen atmosphere at 100° C.for 23 hours. After the reaction mixture was cooled to room temperature,water and a saturated ammonium chloride aqueous solution were added. Theresulting mixture was extracted with ethyl acetate. The organic layerwas dried over anhydrous magnesium sulfate, and then concentrated underreduced pressure. The residue was dissolved with diethyl ether (60 ml),and concentrated hydrochloric acid (10 ml) was added to the resultingsolution, which was then stirred for 2 hours. A 5N sodium hydroxideaqueous solution (24 ml) was added to the reaction mixture to get apH=11, and concentrated under reduced pressure. The residue wasdissolved in dichloromethane and washed with a saturated sodium chlorideaqueous solution. The organic layer was concentrated under reducedpressure. The residue was then purified by silica gel columnchromatography (n-hexane:ethyl acetate=9:1). The purified product wasconcentrated under reduced pressure to thereby obtain 850 mg of oilydark brown 4,5-difluoro-2-propoxyaniline (yield: 38%).

¹H-NMR (CDCl₃) δppm:

1.04 (3H, t, J=7.4 Hz), 1.75-1.86 (2H, m), 3.71 (2H, brs), 3.88 (2H, t,J=6.5 Hz), 6.51 (1H, dd, J=8.0 Hz, 11.5 Hz), 6.60 (1H, dd, J=7.3 Hz,J=11.8 Hz).

REFERENCE EXAMPLE 45 1-(2-Amino-4-fluorobenzoyl)pyrrolidine

A DMF solution (4 ml) of pyrrolidine (1.93 g, 27.1 mmol), a DMF solution(4 ml) of triethylamine (3.79 g, 37.5 mmol), 1-hydroxybenzotriazole(HOBt) (3.11 g, 23.0 mmol), and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (WSC) (3.91g, 20.4 mmol) were added to a DMF solution (4 ml) of 4-fluoroanthranilicacid (2.0 g, 12.8 mmol) in that order. The mixture was stirred at roomtemperature for 14 hours. Water was added to the reaction mixture andthe resulting mixture was extracted with ethyl acetate. The organiclayer was washed with a saturated sodium chloride aqueous solution, andthen concentrated under reduced pressure. The residue was then purifiedby silica gel column chromatography (dichloromethane:methanol=30:1). Thepurified product was concentrated under reduced pressure to therebyobtain 1.65 g of oily orange 1-(2-amino-4-fluorobenzoyl)pyrrolidine(yield: 62%).

¹H-NMR (CDCl₃) δppm:

1.75-2.00 (4H, m), 3.40-3.75 (4H, m), 4.85 (2H, brs), 6.33-6.40 (2H, m),7.14-7.21 (1H, m).

REFERENCE EXAMPLE 46 Ethyl α-(hydroxymethylene)-4-methoxyphenyl acetate

Sodium hydride (60% in oil) (467 mg, 11.7 mmol) was added to a benzenesolution (10 ml) of ethyl 4-methoxyphenyl acetate (2.0 g, 10.3 mmol),while being cooled with ice. The mixture was stirred at room temperaturefor 5 minutes. The stirred mixture was cooled with ice again; ethylformate (1.02 ml, 12.6 mmol) was added thereto, and stirred at roomtemperature for 3 hours. While being cooled with ice, water and ethylacetate were added to the reaction mixture, and then 2N hydrochloricacid (6 ml) was added to separate the reaction mixture into two layers.The organic layer was concentrated under reduced pressure, and theresidue was then purified by silica gel column chromatography(n-hexane:ethyl acetate=4:1). The purified product was concentratedunder reduced pressure to thereby obtain 1.97 g of oily slightlyreddish-brown ethyl α-(hydroxymethylene)-4-methoxyphenyl acetate (yield:86%). The resultant compound undergoes nitrogen substitution, and wasstored in a freezer.

¹H-NMR (CDCl₃) δppm:

1.28 (3H, t, J=7.1 Hz), 3.81 (3H, s), 4.28 (2H, q, J=7.1 Hz), 6.87 (2H,d, J=8.8 Hz), 7.16-7.26 (3H, m), 12.02 (1H, d, J=12.5 Hz).

The compounds of the following Reference Examples 47 to 57 were preparedin the same manner as the above Reference Example 46, usingcorresponding starting materials.

REFERENCE EXAMPLE 47 Ethyl 2,4-dimethoxy-α-(hydroxymethylene)phenylacetate

¹H-NMR (CDCl₃) δppm:

1.21 (3H, t, J=7.1 Hz), 3.76 (3H, s), 3.81 (3H, s), 4.22 (2H, q, J=7.1Hz), 6.43-6.49 (2H, m), 7.00 (1H, d, J=8.9 Hz), 7.12 (1H, d, J=12.6 Hz),11.89 (1H, d, J=12.6 Hz).

REFERENCE EXAMPLE 48 Ethyl 2,4-dichloro-α-(hydroxymethylene)phenylacetate

¹H-NMR (CDCl₃) δppm:

1.15 (3H, t, J=7.2 Hz), 4.22 (2H, q, J=7.2 Hz), 7.11-7.26 (3H, m),7.40-7.43 (1H, m), 12.00 (1H, d, J=12.2 Hz).

REFERENCE EXAMPLE 49 Ethyl α-(hydroxymethylene)-2-methoxyphenyl acetate

¹H-NMR (CDCl₃) δppm:

1.19 (3H, t, J=7.1 Hz), 3.79 (3H, s), 4.21 (2H, q, J=7.1 Hz), 6.86-7.68(5H, m), 11.91 (1H, d, J=12.3 Hz).

REFERENCE EXAMPLE 50 Ethylα-(hydroxymethylene)-2-isopropoxy-4-methoxyphenyl acetate

¹H-NMR (CDCl₃) δppm:

1.20-1.31 (9H, m), 3.80 (3H, s), 4.17 (2H, q, J=7.1 Hz), 4.43-4.47 (1H,m), 6.42-6.46 (2H, m), 6.90-7.12 (2H, m), 11.85 (1H, d, J=12.6 Hz).

REFERENCE EXAMPLE 51 Ethyl α-(hydroxymethylene)-4-methoxy-2-methylphenylacetate

¹H-NMR (CDCl₃) δppm:

1.20 (3H, t, J=7.2 Hz), 2.19 (3H, s), 3.80 (3H, s), 4.22 (2H, q, J=7.2Hz), 6.54-6.75 (2H, m), 7.02-7.26 (2H, m), 11.94 (1H, d, J=12.7 Hz).

REFERENCE EXAMPLE 52 Ethyl 2-fluoro-α-(hydroxymethylene)-4-methoxyphenylacetate

¹H-NMR (CDCl₃) δppm:

1.22 (3H, t, J=7.1 Hz), 3.80 (3H, s), 4.21 (2H, q, J=7.1 Hz), 6.61-6.69(2H, m), 7.03-7.26 (2H, m), 12.05 (1H, d, J=12.3 Hz).

REFERENCE EXAMPLE 53 Ethyl 4-ethoxy-α-(hydroxymethylene)-2-methoxyphenylacetate

¹H-NMR (CDCl₃) δppm:

1.19-1.45 (6H, m), 3.75 (3H, s), 4.00-4.26 (4H, m), 6.42-6.48 (2H, m),6.97-7.26 (2H, m), 11.86 (1H, d, J=12.3 Hz).

REFERENCE EXAMPLE 54 Ethylα-(hydroxymethylene)-4-isopropoxy-2-methoxyphenyl acetate

¹H-NMR (CDCl₃) δppm:

1.20-1.31 (9H, m), 3.75 (3H, s), 4.16 (2H, q, J=7.2 Hz), 4.43-4.47 (1H,m), 6.43-6.48 (2H, m), 6.99-7.22 (2H, m), 11.87 (1H, d, J=12.3 Hz).

REFERENCE EXAMPLE 55 Ethyl4-cyclopropylmethoxy-α-(hydroxymethylene)phenyl acetate

¹H-NMR (CDCl₃) δppm:

0.35-0.37 (4H, m), 1.24 (3H, t, J=7.1 Hz), 3.81-3.83 (2H, m), 4.25 (2H,q, J=7.1 Hz), 6.85-6.91 (2H, m), 7.16-7.27 (3H, m), 12.02 (1H, d, J=12.5Hz).

REFERENCE EXAMPLE 56 Ethyl α-(hydroxymethylene)-4-methylsulfanylphenylacetate

¹H-NMR (CDCl₃) δppm:

1.22 (3H, t, J=7.1 Hz), 2.47 (3H, s), 4.09 (2H, q, J=7.1 Hz), 6.85-6.94(2H, m), 7.16-7.26 (3H, m), 11.99 (1H, d, J=12.3 Hz).

REFERENCE EXAMPLE 57 Ethyl 4-ethoxy-α-(hydroxymethylene)phenyl acetate

¹H-NMR (CDCl₃) δppm:

1.23-1.47 (6H, m), 4.00-4.32 (4H, m), 6.85-6.88 (2H, m), 7.15-7.27 (3H,m), 12.00 (1H, d, J=12.5 Hz).

REFERENCE EXAMPLE 58 Ethyl 4-methoxy-α-propionylphenyl acetate

L-Proline (980 mg, 8.52 mmol), copper (I) iodide (810 mg, 4.26 mmol),and cesium carbonate (27.7 g, 85.2 mmol) were added to adimethylsulfoxide (DMSO) solution (40 ml) of ethyl propionyl acetate(3.8 g, 26.3 mmol) and 4-iodoanisole (5.0 g, 21.3 mmol) in that order.The mixture was stirred under a nitrogen atmosphere at 40 to 45° C. for27 hours. The reaction mixture was cooled to room temperature, and thenwater and ammonium chloride aqueous solution were added. The resultingmixture was extracted with ethyl acetate. The organic layer was washedwith a saturated sodium chloride aqueous solution twice, andconcentrated under reduced pressure. The residue was then purified bysilica gel column chromatography (n-hexane:ethyl acetate=19:1→8:1). Thepurified product was concentrated under reduced pressure to therebyobtain 2.97 g of oily yellow ethyl 4-methoxy-α-propionylphenyl acetate(yield: 56%).

¹H-NMR (CDCl₃) δppm:

1.01-1.11 (3H, m), 1.18-1.31 (3H, m), 2.52-2.61 (2H, m), 3.80 and 3.82(3H, s), 4.15-4.24 (2H, m), 4.65 (0.6H, s), 6.84-7.28 (4H, m), 13.13(0.4H, s).

The compound of the following Reference Example 59 was prepared in thesame manner as the above Reference Example 58, using correspondingstarting materials.

REFERENCE EXAMPLE 59 Ethyl α-acetyl-4-methoxyphenyl acetate

¹H-NMR (CDCl₃) δppm:

1.16-1.29 (3H, m), 1.85 (1.4H, s), 2.17 (1.6H, s), 3.80 and 3.82 (1.4and 1.6H, s), 4.13-4.25 (2H, m), 4.62 (0.6H, s), 6.85-7.28 (4H, m),13.09 (0.4H, s).

REFERENCE EXAMPLE 605-[(5-Fluoro-2-propoxyphenylamino)methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione

Meldrum's acid (5.29 g, 36.7 mmol) was added to methyl orthoformate (31ml), and the mixture was stirred for 2 hours while heating under reflux.The resulting mixture was cooled to 50° C., and5-fluoro-2-propoxyaniline (4.28 g, 25.3 mmol) and methyl orthoformate (3ml) were added thereto. The resulting mixture was stirred for 6 hourswhile heating under reflux. The resulting reaction mixture was thencooled to room temperature, and concentrated under reduced pressure. Theresidue was recrystallized from methanol to thereby obtain 7.61 g ofpowdery pale brown5-[(5-fluoro-2-propoxyphenylamino)methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione(yield: 93%).

¹H-NMR (CDCl₃) δppm:

1.12 (3H, t, J=7.4 Hz), 1.75 (6H, s), 1.85-1.98 (2H, m), 4.02 (2H, t,J=6.3 Hz), 6.86-6.91 (2H, m), 7.06-7.10 (1H, m), 8.60 (1H, d, J=14.6Hz), 11.68 (1H, d, J=14.8 Hz).

The compound of the following Reference Example 61 was prepared in thesame manner as the above Reference Example 60, using correspondingstarting materials.

REFERENCE EXAMPLE 615-[(2-Cyclopropylmethoxy-5-fluorophenylamino)methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione

¹H-NMR (CDCl₃) δppm:

0.39-0.43 (2H, m), 0.65-0.73 (2H, m), 1.31-1.37 (1H, m), 1.75 (6H, s),3.92 (2H, d, J=6.9 Hz), 6.86-6.91 (2H, m), 7.07-7.11 (1H, m), 8.60 (1H,d, J=14.5 Hz), 11.69 (1H, d, J=14.3 Hz).

REFERENCE EXAMPLE 62 5-Fluoro-8-propoxy-1H-quinolin-4-one

5-[(5-Fluoro-2-propoxyphenylamino)methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione(7.6 g, 23.5 mmol) was added to diphenyl ether (15 ml), and the mixturewas heated using a mantle heater, and then kept under reflux for 2hours. After the reaction mixture was cooled to room temperature, ethylacetate (5 ml) and n-hexane (10 ml) were added. The resulting mixturewas stirred and the resultant insoluble matter was collected byfiltration. The filtrate was recrystallized from an ethylacetate-n-hexane mixed solvent to thereby obtain 3.15 g of powdery darkbrown 5-fluoro-8-propoxy-1H-quinolin-4-one (yield: 61%).

¹H-NMR (DMSO-d₆) δppm:

1.03 (3H, t, J=7.3 Hz), 1.74-1.88 (2H, m), 4.07 (2H, t, J=6.4 Hz), 5.97(1H, d, J=7.4 Hz), 6.87 (1H, dd, J=8.8 Hz, 11.9 Hz), 7.13 (1H, dd, J=4.0Hz, J=8.8 Hz), 7.70 (1H, t, J=7.2 Hz), 11.07 (1H, brs).

The compound of the following Reference Example 63 was prepared in thesame manner as the above Reference Example 62, using correspondingstarting materials.

REFERENCE EXAMPLE 63 8-Cyclopropylmethoxy-5-fluoro-1H-quinolin-4-one

¹H-NMR (DMSO-d₆) δppm:

0.34-0.40 (2H, m), 0.55-0.61 (2H, m), 1.27-1.33 (1H, m), 3.98 (2H, d,J=7.0 Hz), 5.97 (1H, d, J=7.4 Hz), 6.86 (1H, dd, J=8.8 Hz, J=11.9 Hz),7.13 (1H, dd, J=4.0 Hz, J=8.8 Hz), 7.71 (1H, t, J=7.4 Hz), 11.10 (1H,brs).

REFERENCE EXAMPLE 64 5-Fluoro-2-methyl-8-propoxy-1H-quinolin-4-one

Amberlyst 15 (1.0 g, a product of Sigma Aldrich Corp.) was added to abenzene solution (200 ml) of 5-fluoro-2-propoxyaniline (10 g, 59 mmol)and ethyl acetoacetate (7.7 g, 59 mmol). The mixture was stirred whileheating under reflux for 6 hours and using a Dean-Stark trap. Thereaction mixture was cooled to room temperature, the resin was removedby filtration, and the filtrate was concentrated under reduced pressure.Diphenyl ether (20 ml) was added to the residue. The mixture was heatedusing a mantle heater and stirred under reflux for 2 hours. After thereaction mixture was cooled to room temperature, insoluble matterobtained by the addition of n-hexane-ethyl acetate (2:1) was collectedby filtration. The substance remaining on the filter was washed withn-hexane-ethyl acetate (2:1), and dried to thereby obtain 6.0 g ofpowdery pale yellow 5-fluoro-2-methyl-8-propoxy-1H-quinolin-4-one(yield: 43%).

¹H-NMR (DMSO-d₆) δppm:

0.97 (3H, t, J=7.3 Hz), 1.77-1.87 (2H, m), 2.34 (3H, s), 4.08 (2H, t,J=6.4 Hz), 5.84 (1H, s), 6.79-6.88 (1H, m), 7.10-7.14 (1H, m), 10.58(1H, brs).

REFERENCE EXAMPLE 65 5-Fluoro-3-iodo-8-propoxy-1H-quinolin-4-one

5-Fluoro-8-propoxy-1H-quinolin-4-one (1.0 g, 4.52 mmol) was suspended inDMF (11 ml), and potassium carbonate (0.7 g, 5.06 mmol) and iodide (1.27g, 5.00 mmol) were added to the suspension. The resulting mixture wasstirred at room temperature for 3 hours. The reaction mixture was pouredinto a sodium thiosulfate (3.94 g, 25 mmol) aqueous solution (45 ml).The mixture was stirred for 5 minutes. Ethyl acetate was added to theresulting reaction mixture and stirred, thereby collecting insolublematter by filtration. The filtrate was separated, and the organic layerwas washed with a saturated sodium chloride aqueous solution, and thenconcentrated under reduced pressure. The residue and the collectedinsoluble matter were combined, and then purified by silica gel columnchromatography (dichloromethane:methanol=50:1→40:1). The purifiedproduct was concentrated to dryness under reduced pressure to therebyobtain 1.25 g of powdery pale dark brown5-fluoro-3-iode-8-propoxy-1H-quinolin-4-one (yield: 80%).

¹H-NMR (DMSO-d₆) δppm:

1.02 (3H, t, J=7.4 Hz), 1.78-1.86 (2H, m), 4.09 (2H, t, J=6.5 Hz), 6.97(1H, dd, J=8.8 Hz, J=11.9 Hz), 7.19 (1H, dd, J=4.0 Hz, J=8.8 Hz), 8.19(1H, s), 11.44 (1H, brs).

The compounds of the following Reference Examples 66 and 67 wereprepared in the same manner as the above Reference Example 65, usingcorresponding starting materials.

REFERENCE EXAMPLE 665-Fluoro-3-iodo-2-methyl-8-propoxy-1H-quinolin-4-one

¹H-NMR (CDCl₃) δppm:

0.97 (3H, t, J=7.4 Hz), 1.78-1.88 (2H, m), 2.70 (3H, s), 6.92-7.00 (1H,m), 7.17-7.22 (1H, m).

REFERENCE EXAMPLE 678-Cyclopropylmethoxy-5-fluoro-3-iodo-1H-quinolin-4-one

¹H-NMR (DMSO-d₆) δppm:

0.36-0.40 (2H, m), 0.56-0.63 (2H, m), 1.28-1.31 (1H, m), 3.99 (2H, d,J=7.0 Hz), 6.97 (1H, dd, J=8.8 Hz, J=11.9 Hz), 7.19 (1H, dd, J=4.0 Hz,J=8.8 Hz), 8.19 (1H, s), 11.48 (1H, brs).

REFERENCE EXAMPLE 688-Cyclopropylmethoxy-1-ethyl-5-fluoro-3-iodo-1H-quinolin-4-one

Potassium carbonate (450 mg, 3.26 mmol) was added to a DMF solution (5ml) of 8-cyclopropylmethoxy-5-fluoro-3-iodo-1H-quinolin-4-one (910 mg,2.53 mmol). The mixture was stirred for 15 minutes at room temperature.Ethyl iodide (0.31 ml, 3.87 mmol) was added thereto, and the resultingmixture was stirred at 60° C. for 2 hours. After the reaction mixturewas cooled to room temperature, water was added, and the resultingmixture was extracted with ethyl acetate. The organic layer wasconcentrated under reduced pressure and the residue was then purified bysilica gel column chromatography (dichloromethane:ethylacetate=40:1→15:1). The purified product was concentrated to drynessunder reduced pressure to thereby obtain 750 mg of powdery pale darkbrown 8-cyclopropylmethoxy-1-ethyl-5-fluoro-3-iodo-1H-quinolin-4-one(yield: 77%).

¹H-NMR (DMSO-d₆) δppm:

0.34-0.38 (2H, m), 0.57-0.64 (2H, m), 1.26-1.36 (4H, m), 3.93 (2H, d,J=7.3 Hz), 4.56 (2H, q, J=7.0 Hz), 7.05 (1H, dd, J=8.9 Hz, J=11.4 Hz),7.24 (1H, dd, J=4.6 Hz, J=9.0 Hz), 8.45 (1H, s).

REFERENCE EXAMPLE 692,2,2-Trifluoro-N-(5-fluoro-2-propoxyphenyl)acetamide

A dichloromethane solution (60 ml) of 5-fluoro-2-propoxyaniline (10.0 g,59.1 mmol) was cooled with ice, and 4triethylamine (16.5 ml) was addedthereto. Then, trifluoroacetic anhydride (14.8 g, 70.5 mmol) was added,and the resulting mixture was stirred at room temperature for 1 hour.Water was added to the reaction mixture, and the resulting mixture wasextracted with dichloromethane. The organic layer was washed with water,and dried over anhydrous sodium sulfate. The resulting dry product wasconcentrated under reduced pressure, and the residue was then purifiedby silica gel column chromatography (n-hexane:ethyl acetate=10:1). Thepurified product was concentrated to dryness under reduced pressure tothereby obtain 15.83 g of powdery white2,2,2-trifluoro-N-(5-fluoro-2-propoxyphenyl)acetamide (yield: 99%).

¹H-NMR (CDCl₃) δppm:

1.03 (3H, t, J=7.5 Hz), 1.79-1.93 (2H, m), 3.98 (2H, t, J=6.5 Hz),6.80-6.86 (2H, m), 8.10-8.12 (1H, m), 8.64 (1H, brs).

REFERENCE EXAMPLE 70 Ethyl ester of4,4,4-trifluoro-3-(5-fluoro-2-propoxyphenylamino) buta-2-enoic acid

Carboethoxymethylene triphenylphosphorane (41.52 g, 119.2 mmol) wasadded to a toluene solution (100 ml) of2,2,2-trifluoro-N-(5-fluoro-2-propoxyphenyl)acetamide (15.83 g, 59.1mmol). The mixture was stirred under a nitrogen atmosphere while heatingunder reflux for 4 hours. The reaction mixture was cooled to roomtemperature, concentrated under reduced pressure, and the residue wasthen purified by silica gel column chromatography (n-hexane:ethylacetate=10:1). The purified product was concentrated under reducedpressure to thereby obtain 19.7 g of oily yellow ethyl ester of4,4,4-trifluoro-3-(5-fluoro-2-propoxyphenylamino)buta-2-enoic acid(yield: 99%).

¹H-NMR (CDCl₃) δppm:

1.02 (3H, t, J=7.5 Hz), 1.28 (3H, t, 7.0 Hz), 1.74-1.88 (2H, m), 3.85(2H, t, J=6.5 Hz), 4.17 (2H, q, J=7.0 Hz), 5.41 (1H, s), 6.77-6.97 (3H,m), 9.77 (1H, brs).

REFERENCE EXAMPLE 715-Fluoro-8-propoxy-2-trifluoromethyl-1H-quinolin-4-one

Diphenyl ether (15 ml) was added to ethyl ester of4,4,4-trifluoro-3-(5-fluoro-2-propoxyphenylamino)buta-2-enoic acid (19.7g, 59.0 mmol), and the mixture was stirred for 1.5 hours while heatingunder reflux. The reaction mixture was cooled to room temperature,n-hexane was added, and the precipitate was collected by filtration. Thesubstance remaining on the filter was washed with n-hexane, and dried tothereby obtain 16.2 g of powdery white5-fluoro-8-propoxy-2-trifluoromethyl-1H-quinolin-4-one (yield: 94%).

¹H-NMR (DMSO-d₆) δppm:

1.00 (3H, t, J=7.5 Hz), 1.76-1.90 (2H, m), 4.07 (2H, t, J=6.5 Hz),7.18-7.32 (3H, m), 12.26 (1H, brs).

REFERENCE EXAMPLE 725-Fluoro-3-iodo-8-propoxy-2-trifluoromethyl-1H-quinolin-4-one

Potassium carbonate (3.73 g, 27 mmol) and iodide (6.85 g, 27 mmol) wereadded to a DMF solution (20 ml) of5-fluoro-8-propoxy-2-trifluoromethyl-1H-quinolin-4-one (6.0 g, 20.7mmol) in that order, and the resulting mixture was stirred at roomtemperature for 1.5 hours. A saturated sodium sulfite aqueous solution(20 ml) and ethyl acetate were added to the reaction mixture, and theprecipitated solid was collected by filtration. The filtrate was washedwith water, and then dried over anhydrous sodium sulfate. The driedfiltrate was concentrated under reduced pressure. The residue and thesubstance collected by the advance filtration were combined, anddissolved in ethanol, and then concentrated. The residue wasrecrystallized from an ethyl acetate-n-hexane mixed solvent to therebyobtain 4.7 g of powdery white5-fluoro-3-iodo-8-propoxy-2-trifluoromethyl-1H-quinolin-4-one (yield:55%).

¹H-NMR (DMSO-d₆) δppm:

0.96 (3H, t, J=7.5 Hz), 1.70-1.80 (2H, m), 3.95 (2H, t, J=6.5 Hz),6.64-6.85 (2H, m), 12.02 (1H, brs).

REFERENCE EXAMPLE 73 1-(5-Bromo-2-cyclopentyloxyphenyl)ethanone

Potassium carbonate (6.55 g, 47.4 mmol), cyclopentyl bromide (8.25 g,55.3 mmol) and DMF (5 ml) were added to a DMF solution (10 ml) of5′-bromo-2′-hydroxyacetophenone (8.5 g, 39.5 mmol), and the resultingmixture was stirred at 60° C. for 4.5 hours. Potassium carbonate (3.0 g,21.7 mmol) and cyclopentyl bromide (2.0 g, 13.4 mmol) were added to theresultant mixture, and stirred at 60° C. for 9 hours. After the reactionmixture was cooled to room temperature, water was added, and theresulting mixture was extracted with ethyl acetate. The organic layerwas washed with a saturated sodium chloride aqueous solution, and thenconcentrated under reduced pressure. The residue was then purified bysilica gel column chromatography (n-hexane:ethyl acetate=9:1). Thepurified product was concentrated under reduced pressure to therebyobtain 11.3 g of oily pale yellow1-(5-bromo-2-cyclopentyloxyphenyl)ethanone (yield: 100%).

¹H-NMR (CDCl₃) δppm:

1.68-1.95 (8H, m), 2.58 (3H, s), 4.83-4.87 (1H, m), 6.83 (1H, d, J=8.9Hz), 7.49 (1H, dd, J=2.6 Hz, 8.9 Hz), 7.82 (1H, d, J=2.6 Hz).

REFERENCE EXAMPLE 74 1-(5-Bromo-2-cyclopentyloxyphenyl)ethanone oxime

1-(5-Bromo-2-cyclopentyloxyphenyl)ethanone (5.0 g, 17.65 mmol) wasdissolved in a mixed solvent of chloroform (18 ml) and methanol (70 ml).Hydroxylamine hydrochloride (1.88 g, 27.0 mmol) and pyridine (4.36 ml,54.1 mmol) were added to the resulting solution, and the mixture wasstirred for 6 hours while heating under reflux. The reaction mixture wascooled to room temperature, and then concentrated under reducedpressure. 2N Hydrochloric acid (13.9 ml) was added to the residue, andthe resulting mixture was extracted with dichloromethane. The organiclayer was washed with a saturated sodium chloride aqueous solution,dried over magnesium sulfate, and concentrated to dryness under reducedpressure. The residue was washed with n-hexane and dried to therebyobtain 4.6 g of powdery white 1-(5-bromo-2-cyclopentyloxyphenyl)ethanoneoxime (yield: 87%).

¹H-NMR (CDCl₃) δppm:

1.65-1.90 (8H, m), 2.17 (3H, s), 4.72-4.76 (1H, m), 6.76 (1H, d, J=8.4Hz), 7.35-7.41 (2H, m), 7.99 (1H, brs).

REFERENCE EXAMPLE 75 N-(5-Bromo-2-cyclopentyloxyphenyl)acetamide

1-(5-Bromo-2-cyclopentyloxyphenyl)ethanone oxime (4.56 g, 15.3 mmol) wassuspended in acetonitrile (100 ml). Indium (III) chloride (507 mg, 2.29mmol) was added thereto, and the resultant was heated under reflux for 2hours under a nitrogen atmosphere. The reaction mixture was cooled toroom temperature, and then concentrated under reduced pressure. Theresidue was extracted with dichloromethane. The organic layer was washedwith a saturated sodium chloride aqueous solution, and then concentratedunder reduced pressure. The residue was then purified by silica gelcolumn chromatography (n-hexane:ethyl acetate=8:1→4:1). The purifiedproduct was concentrated under reduced pressure to thereby obtain 3.41 gof oily pale yellow N-(5-bromo-2-cyclopentyloxyphenyl)acetamide (yield:75%).

¹H-NMR (CDCl₃) δppm:

1.67-1.94 (8H, m), 2.18 (3H, s), 4.75-4.81 (1H, m), 6.72 (1H, d, J=8.7Hz), 7.10 (1H, dd, J=2.3 Hz, 8.7 Hz), 7.67 (1H, brs), 8.55 (1H, d, J=2.3Hz).

REFERENCE EXAMPLE 76 5-Bromo-2-cyclopentyloxyaniline

Concentrated hydrochloric acid (5.8 ml) was added to an ethanol solution(100 ml) of N-(5-bromo-2-cyclopentyloxyphenyl)acetamide (3.4 g, 11.4mmol), and the resulting mixture was stirred for 3 hours while heatingunder reflux. After the reaction mixture was cooled to room temperature,a 5N sodium hydroxide solution (14.2 ml) was added to obtain a pH of 11.The resulting mixture was then extracted with dichloromethane. Theorganic layer was washed with a saturated sodium chloride aqueoussolution, and then concentrated under reduced pressure. The residue wasthen purified by silica gel column chromatography (n-hexane:ethylacetate=4:1). The purified product was concentrated under reducedpressure to thereby obtain 2.97 g of oily pale yellow5-bromo-2-cyclopentyloxyaniline (yield: 100%).

¹H-NMR (CDCl₃) δppm:

1.62-1.89 (8H, m), 3.80 (2H, brs), 4.71-4.75 (1H, m), 6.61 (1H, d, J=8.4Hz), 6.75-6.81 (2H, m).

EXAMPLE 1 5-Fluoro-3-furan-3-yl-8-propoxy-1H-quinolin-4-one

5-Fluoro-3-iodo-8-propoxy-1H-quinolin-4-one (780 mg, 2.24 mmol) wassuspended in a mixed solvent of toluene (10 ml) and methanol (1.6 ml),and furan-3-boronic acid (752 mg), tetrakis triphenylphosphine palladium(130 mg, 0.11 mmol), and a 2N sodium carbonate aqueous solution (2.25ml) were added thereto in that order. The mixture was stirred under anitrogen atmosphere at 110° C. for 20 hours. After the reaction mixturewas cooled to room temperature, water was added, and the resultingmixture was extracted with dichloromethane. The organic layer wasconcentrated under reduced pressure, the residue was then purified bysilica gel column chromatography (dichloromethane:methanol=60:1→50:1).The purified product was concentrated under reduced pressure and wasrecrystallized from ethanol to thereby obtain 180 mg of powdery paleyellow 5-fluoro-3-furan-3-yl-8-propoxy-1H-quinolin-4-one (yield: 58%).Melting point 214-215° C.

¹H-NMR (DMSO-d₆) δppm:

1.02 (3H, J=7.3 Hz), 1.78-1.87 (2H, m), 4.09 (2H, t, J=6.4 Hz),6.87-6.95 (2H, m), 7.13 (1H, dd, J=3.8 Hz, J=8.8 Hz), 7.67 (1H, s), 8.11(1H, s), 8.51 (1H, s), 11.50 (1H, brs).

The compounds of the following Examples 2 to 5 were prepared in the samemanner as the above Example 1, using corresponding starting materials.

EXAMPLE 25-Fluoro-3-(3-fluoro-4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one

Gray Powder (Ethanol)

Melting point 194-195° C.

¹H-NMR (DMSO-d₆) δppm:

1.03 (3H, t, J=7.3 Hz), 1.79-1.87 (2H, m), 3.84 (3H, s), 4.09 (2H, t,J=6.4 Hz), 6.90 (1H, dd, J=8.7 Hz, J=12.1 Hz), 7.12-7.19 (2H, m),7.35-7.39 (1H, m), 7.56 (1H, dd, J=2.0 Hz, J=13.5 Hz), 7.87 (1H, s),11.40 (1H, brs).

EXAMPLE 3 5-Fluoro-8-propoxy-3-thiophen-3-yl-1H-quinolin-4-one

Pale Brown Powder (Ethanol)

Melting point 208-210° C.

¹H-NMR (DMSO-d₆) δppm:

1.02 (3H, t, J=7.4 Hz), 1.75-1.89 (2H, m), 4.08 (2H, t, J=6.4 Hz), 6.90(1H, dd, J=8.7 Hz, J=12.1 Hz), 7.13 (1H, dd, J=3.9 Hz, J=8.8 Hz),7.50-7.57 (2H, m), 8.14 (1H, s), 8.19-8.21 (1H, m), 11.42 (1H, brs).

EXAMPLE 43-(3-Chloro-4-methoxyphenyl)-5-fluoro-8-propoxy-1H-quinolin-4-one

Pale Yellow Powder (Ethanol)

Melting point 217-218° C.

¹H-NMR (DMSO-d₆) δppm:

1.02 (3H, t, J=7.3 Hz), 1.78-1.86 (2H, m), 3.85 (3H, s), 4.08 (2H, t,J=6.4 Hz), 6.90 (1H, dd, J=8.8 Hz, J=12.0 Hz), 7.10-7.15 (2H, m), 7.51(1H, dd, J=2.1 Hz, J=8.5 Hz), 7.74 (1H, d, J=2.1 Hz), 7.87 (1H, s),11.45 (1H, brs).

EXAMPLE 55-Fluoro-8-propoxy-3-(4-trifluoromethoxyphenyl)-1H-quinolin-4-one

Pale Gray Powder (Ethanol)

Melting point 212-214° C.

¹H-NMR (DMSO-d₆) δppm:

1.03 (3H, t, J=7.3 Hz), 1.79-1.87 (2H, m), 4.09 (2H, t, J=6.4 Hz), 6.92(1H, dd, J=8.8 Hz, J=12.0 Hz), 7.16 (1H, dd, J=3.9 Hz, J=8.8 Hz), 7.35(2H, d, J=8.5 Hz), 7.73 (2H, d, J=8.7 Hz), 7.91 (1H, s), 11.45 (1H,brs).

EXAMPLE 6 5-Fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one

Amberlyst 15 (1.0 g, a product of Sigma Aldrich Corp.) was added to abenzene solution (150 ml) of 5-fluoro-2-propoxyaniline (16.25 g, 96.0mmol) and ethyl α-(hydroxymethylene)-4-methoxyphenyl acetate (21.34 g,96.0 mmol). The mixture was heated under reflux for 14 hours while usinga Dean-Stark trap and being stirred. The reaction mixture was cooled toroom temperature, the resin was removed by filtration, and the filtratewas concentrated under reduced pressure. Diphenyl ether (40 ml) wasadded to the residue, and the mixture was heated using a mantle heaterand stirred under reflux for 2 hours. The reaction mixture was cooled toroom temperature and purified directly by silica gel columnchromatography (dichloromethane:methanol=100:0→30:1→20:1). The purifiedproduct was concentrated under reduced pressure, and the residue wasrecrystallized from ethanol to thereby obtain 5.28 g of powdery paleyellow 5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one (yield:17%).

Melting point 196-197° C.

¹H-NMR (DMSO-d₆) δppm:

1.02 (3H, t, J=7.3 Hz), 1.78-1.86 (2H, m), 3.75 (3H, s), 4.07 (2H, t,J=6.4 Hz), 6.83-6.96 (3H, m), 7.11 (1H, dd, J=3.9 Hz, J=8.8 Hz), 7.53(2H, d, J=8.8 Hz), 7.81 (1H, s), 11.50 (1H, brs).

The compounds of the following Examples 7 to 46 were prepared in thesame manner as the above Example 6, using corresponding startingmaterials.

EXAMPLE 7 5-Fluoro-3-(2-methoxyphenyl)-8-propoxy-1H-quinolin-4-one

White Powder (Ethyl Acetate)

Melting point 193-195° C.

¹H-NMR (CDCl₃) δppm:

1.05 (3H, t, J=7.5 Hz), 1.82-1.97 (2H, m), 3.77 (3H, s), 4.05 (2H, t,J=6.3 Hz), 6.77-7.02 (4H, m), 7.26-7.29 (1H, m), 7.42-7.45 (1H, m),7.72-7.74 (1H, m), 8.83 (1H, brs).

EXAMPLE 8 3-(2,4-Dimethoxyphenyl)-5-fluoro-8-propoxy-1H-quinolin-4-one

Pale Yellow Powder (Ethyl Acetate)

Melting point 116-118° C.

¹H-NMR (CDCl₃) δppm:

1.07 (3H, t, J=7.5 Hz), 1.84-1.98 (2H, m), 3.76 (3H, s), 3.84 (3H, s),4.06 (2H, t, J=7.5 Hz), 6.54-6.58 (2H, m), 6.77-6.92 (2H, m), 7.38-7.42(1H, m), 7.72-7.75 (1H, m), 8.79 (1H, brs).

EXAMPLE 9 5-Fluoro-8-isopropoxy-3-(4-methoxyphenyl)-1H-quinolin-4-one

White Powder (Ethyl Acetate)

Melting point 193-194° C.

¹H-NMR (CDCl₃) δppm:

1.39 (6H, d, J=5.0 Hz), 3.79 (3H, s), 4.58 (1H, q, J=5.0 Hz), 6.79-6.92(4H, m), 7.54-7.57 (2H, m), 7.68-7.71 (1H, m), 8.80 (1H, brs).

EXAMPLE 10 3-(2,4-Dichlorophenyl)-5-fluoro-8-propoxy-1H-quinolin-4-one

White Powder (Ethyl Acetate)

Melting point 256-259° C.

¹H-NMR (DMSO-d₆) δppm:

1.01 (3H, t, J=7.5 Hz), 1.79-1.87 (2H, m), 4.08 (2H, t, J=6.3 Hz),6.88-6.98 (1H, m), 6.96-7.72 (1H, m), 7.37-7.47 (2H, m), 7.65-7.67 (1H,m), 7.75-7.77 (1H, m), 11.42 (1H, brs).

EXAMPLE 11 8-Ethoxy-5-fluoro-3-(4-methoxyphenyl)-1H-quinolin-4-one

Pale Yellow Powder (Ethyl Acetate)

Melting point 155-156° C.

¹H-NMR (CDCl₃) δppm: 1.46 (3H, t, J=7.5 Hz), 3.81 (3H, s), 4.14 (2H, q,J=7.5 Hz), 6.77-6.94 (4H, m), 7.54-7.60 (2H, m), 7.71-7.73 (1H, m), 9.02(1H, brs).

EXAMPLE 12 3-(2,4-Dimethoxyphenyl)-8-ethoxy-5-fluoro-1H-quinolin-4-one

Pale Yellow Powder (Ethyl Acetate)

Melting point 154-155° C.

¹H-NMR (CDCl₃) δppm:

1.44 (3H, t, J=7.5 Hz), 3.73 (3H, s), 3.81 (3H, s), 4.12 (2H, q, J=7.5Hz), 6.50-6.53 (2H, m), 6.54-6.89 (2H, m), 7.35-7.39 (1H, m), 7.69-7.72(1H, m), 8.97 (1H, brs).

EXAMPLE 13 3-(2,4-Dichlorophenyl)-8-ethoxy-5-fluoro-1H-quinolin-4-one

Pale Yellow Powder (Ethyl Acetate)

Melting point 236-237° C.

¹H-NMR (DMSO-d₆) δppm:

1.40 (3H, t, J=7.5 Hz), 4.17 (2H, q, J=7.5 Hz), 6.88-7.00 (1H, m),7.22-7.32 (1H, m), 7.38-7.45 (2H, m), 7.64-7.65 (1H, m), 7.74-7.75 (1H,m), 11.40 (1H, brs).

EXAMPLE 145-Fluoro-3-(4-methoxyphenyl)-8-morpholin-4-yl-1H-quinolin-4-one

Pale Yellow Powder (Ethyl Acetate)

Melting point 249-251° C.

¹H-NMR (CDCl₃) δppm:

2.75-3.22 (4H, m), 3.65-4.15 (4H, m), 6.85-6.93 (3H, m), 7.34-7.40 (1H,m), 7.54-7.58 (2H, m), 7.74-7.77 (1H, m), 10.02 (1H, brs).

EXAMPLE 155-Fluoro-3-(2-isopropoxy-4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one

White Powder (Ethyl Acetate)

Melting point 204-206° C.

¹H-NMR (CDCl₃) δppm:

1.09 (3H, t, J=6.3 Hz), 1.23 (3H, s), 1.26 (3H, s), 1.87-2.01 (2H, m),3.83 (3H, s), 4.08 (2H, t, J=6.3 Hz), 4.34-4.50 (1H, m), 6.55-6.60 (2H,m), 6.78-6.93 (2H, m), 7.50 (1H, d, J=7.5 Hz), 7.80 (1H, d, J=7.5 Hz),8.73 (1H, brs).

EXAMPLE 165-Fluoro-3-(4-methoxy-2-methylphenyl)-8-propoxy-1H-quinolin-4-one

White Powder (Ethyl Acetate)

Melting point 197-199° C.

¹H-NMR (CDCl₃) δppm:

1.06 (3H, t, J=6.3 Hz), 1.80-2.00 (2H, m), 2.24 (3H, s), 3.80 (3H, s),4.07 (2H, t, J=6.3 Hz), 6.70-6.94 (4H, m), 7.07 (1H, d, J=7.5 Hz), 7.54(1H, d, J=7.5 Hz), 8.80 (1H, brs).

EXAMPLE 175-Fluoro-3-(2-fluoro-4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one

White Powder (Ethyl Acetate-ethanol)

Melting point 230-232° C.

¹H-NMR (CDCl₃) δppm:

1.05 (3H, t, J=7.5 Hz), 1.80-2.00 (2H, m), 3.80 (3H, s), 4.06 (2H, t,J=7.5 Hz), 6.64-6.93 (4H, m), 7.53-7.60 (1H, m), 7.74-7.78 (1H, m), 8.86(1H, brs).

EXAMPLE 185-Fluoro-3-(4-methoxyphenyl)-8-pyrrolidin-1-yl-1H-quinolin-4-one

Pale Brown Powder (Ethyl Acetate-n-hexane)

Melting point 100-105° C.

¹H-NMR (CDCl₃) δppm:

1.90-2.08 (4H, m), 3.01-3.20 (4H, m), 3.81 (3H, s), 6.81-6.94 (3H, m),7.29-7.34 (1H, m), 7.55-7.60 (2H, m), 7.74-7.76 (1H, m), 9.41 (1H, brs).

EXAMPLE 193-(4-Ethoxy-2-methoxyphenyl)-5-fluoro-8-propoxy-1H-quinolin-4-one

Pale Brown Powder (Ethyl Acetate)

Melting point 118-120° C.

¹H-NMR (CDCl₃) δppm:

1.06 (3H, t, J=7.5 Hz), 1.39 (3H, t, J=7.5 Hz), 1.83-1.98 (2H, m), 3.75(3H, s), 4.00-4.14 (4H, m), 6.51-6.55 (2H, m), 6.76-6.91 (2H, m), 7.38(1H, d, J=6.2 Hz), 7.72 (1H, d, J=6.2 Hz), 8.65 (1H, brs).

EXAMPLE 205-Fluoro-3-(4-isopropoxy-2-methoxyphenyl)-8-propoxy-1H-quinolin-4-one

White Powder (Ethyl Acetate-n-hexane)

Melting point 113-115° C.

¹H-NMR (CDCl₃) δppm:

1.04 (3H, t, J=7.5 Hz), 1.33 (3H, s), 1.36 (3H, s), 1.80-1.95 (2H, m),3.72 (3H, s), 4.03 (2H, t, J=7.5 Hz), 4.50-4.71 (1H, m), 6.49-6.53 (2H,m), 6.78-6.86 (2H, m), 7.34-7.38 (1H, m), 7.42-7.74 (1H, m), 8.82 (1H,brs).

EXAMPLE 21 5,6-Difluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one

Pale Brown Powder (Ethyl Acetate-n-hexane)

Melting point 198-200° C.

¹H-NMR (DMSO-d₆) δppm:

1.02 (3H, t, J=7.3 Hz), 1.78-1.86 (2H, m), 3.75 (3H, s), 4.11 (2H, t,J=6.4 Hz), 6.93 (2H, d, J=8.8 Hz), 7.38 (1H, dd, J=6.5 Hz, J=12.3 Hz),7.54 (2H, d, J=8.8 Hz), 7.81 (1H, s), 11.50 (1H, brs).

EXAMPLE 22 8-Bromo-5-fluoro-3-(4-methoxyphenyl)-1H-quinolin-4-one

Pale Yellow Powder (Ethyl Acetate)

Melting point 134-135° C.

¹H-NMR (DMSO-d₆) δppm:

3.78 (3H, s), 6.94-7.02 (3H, m), 7.52 (2H, d, J=6.3 Hz), 7.84 (1H, s),7.89-8.00 (1H, m), 11.20 (1H, brs).

EXAMPLE 235-Fluoro-3-(4-methoxyphenyl)-8-(pyrrolidin-1-carbonyl)-1H-quinolin-4-one

Orange Powder (Ethyl Acetate)

Melting point 236-237° C.

¹H-NMR (DMSO-d₆) δppm:

1.77-1.91 (4H, m), 3.29-3.34 (2H, m), 3.54-3.59 (2H, m), 3.76 (3H, s),6.94 (2H, d, J=8.7 Hz), 7.02 (1H, dd, J=8.3 Hz, J=11.8 Hz), 7.53 (2H, d,J=8.7 Hz), 7.71 (1H, dd, J=5.1 Hz, J=8.3 Hz), 7.88 (1H, s), 11.26 (1H,s).

EXAMPLE 248-Cyclopropylmethoxy-5-fluoro-3-(4-methoxyphenyl)-1H-quinolin-4-one

Pale Yellow Powder (Ethyl Acetate-ethanol)

Melting point 190-191° C.

¹H-NMR (DMSO-d₆) δppm:

0.33-0.39 (2H, m), 0.55-0.62 (2H, m), 1.26-1.34 (1H, m), 3.75 (3H, s),3.99 (2H, d, J=7.0 Hz), 6.83-6.95 (3H, m), 7.12 (1H, dd, J=3.8 Hz, J=8.8Hz), 7.53 (2H, d, J=8.6 Hz), 7.82 (1H, s), 11.34 (1H, brs).

EXAMPLE 258-(N-Cyclohexyl-N-methylamino)-5-fluoro-3-(4-methoxyphenyl)-1H-quinolin-4-one

Pale Yellow Powder (Ethyl Acetate)

Melting point 224-225° C.

¹H-NMR (DMSO-d₆) δppm:

1.00-1.24 (5H, m), 1.53-1.99 (5H, m), 2.65 (3H, s), 3.78 (3H, s),6.92-6.99 (3H, m), 7.50-7.57 (3H, s), 7.87 (1H, s), 10.93 (1H, brs).

EXAMPLE 26N-{3-[5-Fluoro-3-(4-methoxyphenyl)-4-oxo-1,4-dihydroquinolin-8-yloxy]propyl}acetamide

Pale Brown Powder (Ethanol)

Melting point 229-231° C.

¹H-NMR (DMSO-d₆) δppm:

1.80 (3H, s), 1.91-1.96 (2H, m), 3.24-3.31 (2H, m), 3.74 (3H, s), 4.12(2H, t, J=5.6 Hz), 6.84-7.13 (4H, m), 7.53 (2H, d, J=8.6 Hz), 7.83 (1H,s), 8.01 (1H, brs), 11.40 (1H, brs).

EXAMPLE 27N-{3-[5-Fluoro-3-(4-methoxyphenyl)-4-oxo-1,4-dihydroquinolin-8-yloxy]propyl}methanesulfonamide

Pale Brown Powder (Ethanol)

Melting point 120-121° C.

¹H-NMR (DMSO-d₆) δppm:

1.96-2.06 (2H, m), 2.88 (3H, s), 3.10-3.30 (2H, m), 3.75 (3H, s), 4.18(2H, t, J=5.9 Hz), 6.85-6.95 (3H, m), 7.00-7.16 (2H, m), 7.54 (2H, d,J=8.7 Hz), 7.82 (1H, s), 11.34 (1H, brs).

EXAMPLE 285-Fluoro-8-(N-isobutyl-N-methylamino)-3-(4-methoxyphenyl)-1H-quinolin-4-one

White Powder (Ethyl Acetate)

Melting point 144-145° C.

¹H-NMR (DMSO-d₆) δppm:

0.86 (3H, s), 0.91 (3H, s), 1.61-1.67 (1H, m), 2.61 (3H, s), 2.80 (2H,d, J=6.75 Hz), 3.79 (3H, s), 6.91-6.99 (3H, m), 7.46-7.57 (3H, m), 7.88(1H, s), 11.02 (1H, brs).

EXAMPLE 295-Fluoro-8-(N-isopropyl-N-methylamino)-3-(4-methoxyphenyl)-1H-quinolin-4-one

White Powder (Ethyl Acetate)

Melting point 267-269° C.

¹H-NMR (DMSO-d₆) δppm:

1.04 (3H, s), 1.06 (3H, s), 2.62 (3H, s), 3.10-3.18 (1H, m), 3.76 (3H,s), 6.90-6.98 (3H, m), 7.47-7.55 (3H, m), 7.85 (1H, s), 10.94 (1H, brs).

EXAMPLE 305-Fluoro-3-(4-methoxyphenyl)-8-(N-methyl-N-propylamino)-1H-quinolin-4-one

Pale Yellow Powder (Ethyl Acetate)

Melting point 145-146° C.

¹H-NMR (DMSO-d₆) δppm:

0.79 (3H, t, J=7.5 Hz), 1.31-1.45 (2H, m), 2.63 (3H, s), 2.85 (2H, t,J=7.5 Hz), 3.76 (3H, s), 6.89-6.97 (3H, m), 7.43-7.54 (3H, m), 7.82 (1H,s), 11.07 (1H, brs).

EXAMPLE 315-Fluoro-3-(4-methoxyphenyl)-8-(4,4,4-trifluorobutoxy)-1H-quinolin-4-one

White Powder (Ethyl Acetate)

Melting point 171-172° C.

¹H-NMR (DMSO-d₆) δppm:

1.99-2.08 (2H, m), 2.48-2.61 (2H, m), 3.74 (3H, s), 4.17 (2H, t, J=5.9Hz), 6.84-6.94 (3H, m), 7.11 (1H, dd, J=3.8 Hz, J=8.8 Hz), 7.53 (2H, d,J=8.7 Hz), 7.82 (1H, s), 11.40 (1H, brs).

EXAMPLE 321-{3-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-1,4-dihydroquinolin-8-yloxy]propyl}-1,3,3-trimethylurea

Brown Amorphous Solid (Diethyl Ether)

¹H-NMR (DMSO-d₆) δppm:

2.00-2.05 (2H, m), 2.63 (6H, s), 2.74 (3H, s), 3.20-3.40 (2H, m), 3.76(3H, s), 4.12 (2H, t, J=6.0 Hz), 6.85-6.96 (3H, m), 7.14 (1H, dd, J=3.9Hz, J=8.8 Hz), 7.55 (2H, d, J=8.7 Hz), 7.81 (1H, s), 11.40 (1H, brs).

EXAMPLE 33 3-(4-Ethoxyphenyl)-5-fluoro-8-propoxy-1H-quinolin-4-one

Pale Yellow Powder (Ethyl Acetate)

Melting point 203-205° C.

¹H-NMR (DMSO-d₆) δppm:

1.02 (3H, t, J=7.3 Hz), 1.13 (3H, t, J=7.0 Hz), 1.76-1.91 (2H, m),3.99-4.13 (4H, m), 6.84-6.94 (3H, m), 7.12-7.17 (1H, m), 7.50 (2H, d,J=7.5 Hz), 7.79 (1H, s), 11.25 (1H, brs).

EXAMPLE 345-Fluoro-8-[N-(2-methoxyethyl)-N-methylamino]-3-(4-methoxyphenyl)-1H-quinolin-4-onehydrochloride

Pale Yellow Powder (Ethyl Acetate)

Melting point 100-101° C.

¹H-NMR (DMSO-d₆) δppm:

2.78 (3H, s), 3.08 (2H, t, J=5.3 Hz), 3.33 (3H, s), 3.49 (2H, t, J=5.3Hz), 3.81 (3H, s), 6.94-7.02 (3H, m), 7.50-7.62 (3H, m), 8.00 (1H, s),11.16 (1H, brs).

EXAMPLE 353-(4-Cyclopropylmethoxyphenyl)-5-fluoro-8-propoxy-1H-quinolin-4-one

White Powder (Ethyl Acetate)

Melting point 162-163° C.

¹H-NMR (DMSO-d₆) δppm:

0.30-0.35 (2H, m), 0.54-0.58 (2H, m), 1.01 (3H, t, J=7.5 Hz), 1.10-1.30(1H, m), 1.72-1.91 (2H, m), 3.80 (2H, d, J=7.0 Hz), 4.07 (2H, t, J=6.4Hz), 6.84-6.93 (3H, m), 7.11-7.16 (1H, m), 7.50 (2H, d, J=8.8 Hz), 7.79(1H, s), 11.25 (1H, brs).

EXAMPLE 365-Fluoro-8-(2-methoxyethoxy)-3-(4-methoxyphenyl)-1H-quinolin-4-one

Pale Yellow Powder (Ethyl Acetate)

Melting point 142-144° C.

¹H-NMR (DMSO-d₆) δppm:

3.31 (3H, s), 3.70-3.80 (2H, m), 3.75 (3H, s), 4.20-4.30 (2H, m),6.84-6.94 (3H, m), 7.16 (1H, dd, J=3.6 Hz, J=8.7 Hz), 7.53 (2H, d, J=8.4Hz), 7.82 (1H, s), 11.10 (1H, brs).

EXAMPLE 378-Cyclopentyloxy-5-fluoro-3-(4-methoxyphenyl)-1H-quinolin-4-one

Pale Yellow Powder (Ethyl Acetate)

Melting point 213-215° C.

¹H-NMR (DMSO-d₆) δppm:

1.50-1.70 (2H, m), 1.71-2.00 (6H, m), 3.75 (3H, s), 4.92-4.95 (1H, m),6.83-6.95 (3H, m), 7.09 (1H, dd, J=3.9 Hz, J=8.8 Hz), 7.53 (2H, d, J=8.6Hz), 7.80 (1H, s), 11.20 (1H, brs).

EXAMPLE 385-Fluoro-3-(4-methylsulfanylphenyl)-8-propoxy-1H-quinolin-4-one

Pale Yellow Powder (Ethyl Acetate)

Melting point 198-199° C.

¹H-NMR (CDCl₃) δppm:

1.07 (3H, t, J=7.4 Hz), 1.85-2.04 (2H, m), 2.50 (3H, s), 4.07 (2H, t,J=6.6 Hz), 6.80-6.94 (2H, m), 7.27-7.31 (2H, m), 7.56 (2H, d, J=8.4 Hz),7.74 (1H, d, J=8.2 Hz), 8.81 (1H, brs).

EXAMPLE 395-Fluoro-3-(4-methoxyphenyl)-8-(tetrahydrofuran-2-ylmethoxy)-1H-quinolin-4-one

Pale Yellow Powder (Ethyl Acetate)

Melting point 108-110° C.

¹H-NMR (DMSO-d₆) δppm:

1.67-1.75 (1H, m), 1.81-1.90 (2H, m), 2.02-2.09 (1H, m), 3.65-3.83 (2H,m), 3.75 (3H, s), 4.10 (2H, d, J=4.6 Hz), 4.25-4.29 (1H, m), 6.84-6.95(3H, m), 7.17 (1H, dd, J=3.8 Hz, J=8.8 Hz), 7.53 (2H, d, J=8.7 Hz), 7.82(1H, s), 11.20 (1H, brs).

EXAMPLE 405-Fluoro-3-(4-methoxyphenyl)-8-propylsulfanyl-1H-quinolin-4-one

White Powder (Ethyl Acetate)

Melting point 173-174° C.

¹H-NMR (DMSO-d₆) δppm:

0.90 (3H, t, J=7.3 Hz), 1.40-1.52 (2H, m), 2.79 (2H, t, J=7.2 Hz), 3.77(3H, s), 6.93-7.04 (3H, m), 7.51-7.55 (2H, m), 7.79-7.87 (2H, m), 11.24(1H, brs).

EXAMPLE 418-Cyclobutylmethoxy-5-fluoro-3-(4-methoxyphenyl)-1H-quinolin-4-one

Pale Yellow Powder (Ethyl Acetate)

Melting point 193-194° C.

¹H-NMR (DMSO-d₆) δppm:

1.79-1.93 (4H, m), 2.04-2.09 (2H, m), 2.76-2.81 (1H, m), 3.74 (3H, s),4.08 (2H, d, J=6.8 Hz), 6.83-6.93 (3H, m), 7.11 (1H, dd, J=3.8 Hz, J=8.8Hz), 7.52 (2H, d, J=8.6 Hz), 7.82 (1H, s), 11.20 (1H, brs).

EXAMPLE 42 8-tert-Butoxy-5-fluoro-3-(4-methoxyphenyl)-1H-quinolin-4-one

Pale Brown Powder (Ethyl Acetate-diethyl Ether)

Melting point 206-208° C.

¹H-NMR (DMSO-d₆) δppm:

1.40 (9H, s), 3.76 (3H, s), 6.84-6.96 (3H, m), 7.31 (1H, dd, J=4.3 Hz,J=8.8 Hz), 7.54 (2H, d, J=8.8 Hz), 7.82 (1H, s), 10.95 (1H, brs).

EXAMPLE 43 5-Fluoro-8-methoxy-3-(4-methoxyphenyl)-1H-quinolin-4-one

Pale Dark Brown Powder (Ethyl Acetate)

¹H-NMR (DMSO-d₆) δppm:

3.76 (3H, s), 3.95 (3H, s), 6.87-6.95 (3H, m), 7.15 (1H, dd, J=3.8 Hz,J=8.8 Hz), 7.54 (2H, d, J=8.7 Hz), 7.76 (1H, s), 11.50 (1H, brs).

EXAMPLE 445-Fluoro-8-methoxymethoxy-3-(4-methoxyphenyl)-1H-quinolin-4-one

Pale Dark Brown Powder (Dichloromethane-methanol)

¹H-NMR (CDCl₃) δppm:

3.44 (3H, s), 3.76 (3H, s), 5.20 (2H, s), 6.76-6.87 (3H, m), 7.18-7.23(1H, m), 7.52 (2H, d, J=7.8 Hz), 7.69 (1H, s), 9.68 (1H, brs).

EXAMPLE 458-(3-Benzyloxypropoxy)-5-fluoro-3-(4-methoxyphenyl)-1H-quinolin-4-one

Dark Brown Amorphous Solid

¹H-NMR (DMSO-d₆) δppm:

2.08-2.13 (2H, m), 3.68 (2H, t, J=6.2 Hz), 3.77 (3H, s), 4.22 (2H, t,J=6.0 Hz), 4.48 (2H, s), 6.84-6.97 (3H, m), 7.13-7.18 (1H, m), 7.21-7.29(5H, m), 7.55 (2H, d, J=8.7 Hz), 7.76 (1H, s), 11.25 (1H, brs).

EXAMPLE 468-(2-Benzyloxypropoxy)-5-fluoro-3-(4-methoxyphenyl)-1H-quinolin-4-one

Dark Brown Amorphous Solid

¹H-NMR (DMSO-d₆) δppm:

1.32 (3H, d, J=6.2 Hz), 3.76 (3H, s), 3.98-4.24 (3H, m), 4.54-4.69 (2H,m), 6.84-6.96 (3H, m), 7.16-7.30 (6H, m), 7.54 (2H, d, J=8.7 Hz), 7.78(1H, s), 11.19 (1H, brs).

EXAMPLE 478-Cyclopropylmethoxy-5-fluoro-3-(4-methoxyphenyl)-2-methyl-1H-quinolin-4-one

Amberlyst 15 (350 mg, a product of Sigma Aldrich Corp.) was added to abenzene solution (40 ml) of 2-cyclopropylmethoxy-5-fluoroaniline (760mg, 4.2 mmol) and ethyl α-acetyl-4-methoxyphenyl acetate (1.0 g, 4.2mmol), and the mixture was heated under reflux for 19 hours while usinga Dean-Stark trap and being stirred. The reaction mixture was cooled toroom temperature, the resin was removed by filtration, and the filtratewas concentrated under reduced pressure. Diphenyl ether (2.2 ml) wasadded to the residue, and the mixture was heated using a mantle heaterand then stirred for 1 hour under reflux. The reaction mixture wascooled to room temperature and purified directly by silica gel columnchromatography (dichloromethane:methanol=80:1→60:1). The purifiedproduct was concentrated under reduced pressure, and the residue wasrecrystallized from ethyl acetate to thereby obtain 120 mg of powderypale yellow8-cyclopropylmethoxy-5-fluoro-3-(4-methoxyphenyl)-2-methyl-1H-quinolin-4-one(yield: 8%). Melting point 167-169° C.

¹H-NMR (DMSO-d₆) δppm:

0.35-0.39 (2H, m), 0.54-0.61 (2H, m), 1.31-1.37 (1H, m), 2.23 (3H, s),3.76 (3H, s), 4.02 (2H, d, J=7.0 Hz), 6.80-6.94 (3H, m), 7.08-7.18 (3H,m), 10.62 (1H, brs).

The compound of the following Example 48 was prepared in the same manneras the above Example 47, using corresponding starting materials.

EXAMPLE 482-Ethyl-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one

Pale Brown Powder (Ethyl Acetate-n-hexane)

Melting point 169-171° C.

¹H-NMR (DMSO-d₆) δppm:

0.98-1.05 (6H, m), 1.80-1.89 (2H, m), 2.56 (2H, t, J=7.5 Hz), 3.77 (3H,s), 4.13 (2H, t, J=6.6 Hz), 6.81-6.95 (3H, m), 7.05-7.17 (3H, m), 10.40(1H, brs).

EXAMPLE 49 5-Fluoro-8-propoxy-3-pyridin-3-yl-1H-quinolin-4-one

5-Fluoro-3-iodo-8-propoxy-1H-quinolin-4-one (600 mg, 1.73 mmol) wassuspended in 1,2-dimethoxyethane (12 ml). 3-pyridine boronic acid (752mg), 1,1′-bis(diphenylphosphino)ferrocene dichloropalladium(II)-dichloromethane complex (PdCl₂(DPPF)) (76 mg, 0.093 mmol),and 2N sodium carbonate aqueous solution (2.54 ml) were added to theresulting suspension in that order. The mixture was stirred at 90° C.for 2 hours under a nitrogen atmosphere. After the reaction mixture wascooled to room temperature, water was added, and the resulting mixturewas extracted with ethyl acetate. The organic layer was concentratedunder reduced pressure, and the residue was then purified by silica gelcolumn chromatography (dichloromethane:methanol=15:1). The purifiedproduct was concentrated under reduced pressure, and then recrystallizedfrom ethanol to thereby obtain 185 mg of powdery pale brown5-fluoro-8-propoxy-3-pyridin-3-yl-1H-quinolin-4-one (yield: 36%).Melting point 234-236° C.

¹H-NMR (DMSO-d₆) δppm:

1.01 (3H, t, J=7.3 Hz), 1.77-1.86 (2H, m), 4.08 (2H, t, J=6.4 Hz), 6.93(1H, dd, J=8.8 Hz, J=12.0 Hz), 7.13-7.18 (1H, m), 7.37-7.42 (1H, m),7.97 (1H, s), 8.01-8.05 (1H, m), 8.44-8.46 (1H, m), 8.77 (1H, d, J=2.1Hz), 11.55 (1H, brs).

The compounds of the following Examples 50 to 66 were prepared in thesame manner as the above Example 49, using corresponding startingmaterials.

EXAMPLE 503-(4-Ethoxy-3-fluorophenyl)-5-fluoro-8-propoxy-1H-quinolin-4-one

Pale Yellow Powder (Ethanol)

Melting point 176-177° C.

¹H-NMR (DMSO-d₆) δppm:

1.02 (3H, t, J=7.3 Hz), 1.33 (3H, t, J=6.9 Hz), 1.75-1.89 (2H, m),4.05-4.14 (4H, m), 6.90 (1H, dd, J=8.7 Hz, J=12.1 Hz), 7.09-7.16 (2H,m), 7.32-7.36 (1H, m), 7.52-7.58 (1H, m), 7.87 (1H, s), 11.45 (1H, s).

EXAMPLE 51 5-Fluoro-8-propoxy-3-pyridin-4-yl-1H-quinolin-4-one

Pale Brown Powder (Ethanol)

Melting point 259-261° C.

¹H-NMR (DMSO-d₆) δppm:

1.02 (3H, t, J=7.3 Hz), 1.78-1.86 (2H, m), 4.09 (2H, t, J=6.4 Hz), 6.96(1H, dd, J=8.8 Hz, J=12.0 Hz), 7.19 (1H, dd, J=3.8 Hz, J=8.8 Hz), 7.71(2H, d, J=6.1 Hz), 8.06 (1H, s), 8.52 (2H, d, J=6.1 Hz), 11.50 (1H,brs).

EXAMPLE 52 5-Fluoro-3-(4-phenoxyphenyl)-8-propoxy-1H-quinolin-4-one

Pale Brown Powder (Ethanol)

Melting point 228-230° C.

¹H-NMR (DMSO-d₆) δppm:

1.01 (3H, t, J=7.3 Hz), 1.77-1.85 (2H, m), 4.07 (2H, t, J=6.2 Hz), 6.90(1H, dd, J=8.8 Hz, J=12.1 Hz), 6.97-7.02 (4H, m), 7.10-7.15 (2H, m),7.34-7.63 (4H, m), 7.88 (1H, s), 11.40 (1H, brs).

EXAMPLE 53 3-(4-Ethylphenyl)-5-fluoro-8-propoxy-1H-quinolin-4-one

White Powder (Ethyl Acetate)

Melting point 153-154° C.

¹H-NMR (DMSO-d₆) δppm:

1.02 (3H, t, J=7.3 Hz), 1.17 (3H, t, J=7.5 Hz), 1.78-1.86 (2H, m), 2.59(2H, q, J=7.5 Hz), 4.08 (2H, t, J=6.4 Hz), 6.89 (1H, dd, J=8.8 Hz,J=12.1 Hz), 7.10-7.21 (3H, m), 7.50 (2H, d, J=8.0 Hz), 7.83 (1H, s),11.40 (1H, brs).

EXAMPLE 54 3-(4-Acetylphenyl)-5-fluoro-8-propoxy-1H-quinolin-4-one

Pale Red Powder (Ethyl Acetate)

Melting point 180-181° C.

¹H-NMR (DMSO-d₆) δppm:

0.95 (3H, t, J=7.5 Hz), 1.71-1.83 (2H, m), 2.51 (3H, m), 4.02 (2H, t,J=6.6 Hz), 6.84-6.91 (1H, m), 7.10-7.14 (1H, m), 7.72 (2H, d, J=8.4 Hz),7.87-7.90 (3H, m), 11.40 (1H, brs).

EXAMPLE 55 Methyl4-(5-fluoro-4-oxo-8-propoxy-1,4-dihydroquinolin-3-yl)benzoate

White Powder (Ethyl Acetate)

Melting point 201-202° C.

¹H-NMR (DMSO-d₆) δppm:

1.01 (3H, t, J=7.3 Hz), 1.77-1.91 (2H, m), 3.86 (3H, s), 4.09 (2H, t,J=6.5 Hz), 6.90-6.99 (1H, m), 7.17-7.22 (1H, m), 7.80 (2H, d, J=8.5 Hz),7.94-7.98 (3H, m), 11.48 (1H, brs).

EXAMPLE 565-Fluoro-8-propoxy-3-[4-(pyrrolidine-1-carbonyl)phenyl]-1H-quinolin-4-one

Pale Red Powder (Ethyl Acetate)

Melting point 236-237° C.

¹H-NMR (DMSO-d₆) δppm:

1.02 (3H, t, J=7.4 Hz), 1.79-1.89 (6H, m), 3.43-3.49 (4H, m), 4.08 (2H,t, J=6.5 Hz), 6.89-6.97 (1H, m), 7.15-7.20 (1H, m), 7.51 (2H, d, J=8.6Hz), 7.67 (2H, d, J=8.6 Hz), 7.90 (1H, s), 11.40 (1H, brs).

EXAMPLE 574-(5-Fluoro-4-oxo-8-propoxy-1,4-dihydroquinolin-3-yl)-N,N-dimethylbenzamide

Pale Brown Powder (Ethyl Acetate)

Melting point 235-237° C.

¹H-NMR (DMSO-d₆) δppm:

1.02 (3H, t, J=7.4 Hz), 1.80-1.89 (2H, m), 2.97 (6H, s), 4.08 (2H, t,J=6.4 Hz), 6.89-6.93 (1H, m), 7.15-7.20 (1H, m), 7.39 (2H, d, J=8.0 Hz),7.67 (2H, d, J=8.0 Hz), 7.90 (1H, s), 11.41 (1H, brs).

EXAMPLE 58 5-Fluoro-3-furan-2-yl-8-propoxy-1H-quinolin-4-one

Pale Brown Powder (Ethyl Acetate)

Melting point 210-212° C.

¹H-NMR (DMSO-d₆) δppm:

1.02 (3H, t, J=7.4 Hz), 1.78-1.90 (2H, m), 4.10 (2H, t, J=6.6 Hz),6.54-6.56 (1H, m), 6.90-6.99 (1H, m), 7.15-7.21 (2H, m), 7.64-7.65 (1H,m), 8.20 (1H, s), 11.47 (1H, brs).

EXAMPLE 59 5-Fluoro-8-propoxy-3-thiophen-2-yl-1H-quinolin-4-one

Pale Red Powder (Ethyl Acetate)

Melting point 211-213° C.

¹H-NMR (DMSO-d₆) δppm:

1.02 (3H, t, J=7.5 Hz), 1.78-1.90 (2H, m), 4.10 (2H, t, J=6.5 Hz),6.92-7.20 (3H, m), 7.41-7.59 (2H, m), 8.34 (1H, s), 11.63 (1H, brs).

EXAMPLE 603-(5-Fluoro-4-oxo-8-propoxy-1,4-dihydroquinolin-3-yl)thiophene-2-carbaldehyde

White Powder (Ethyl Acetate)

Melting point 190-191° C.

¹H-NMR (DMSO-d₆) δppm:

1.01 (3H, t, J=7.4 Hz), 1.79-1.88 (2H, m), 4.08 (3H, t, J=6.5 Hz),6.92-7.00 (1H, m), 7.18-7.23 (1H, m), 7.32 (1H, d, J=5.0 Hz), 7.98 (1H,s), 8.04-8.06 (1H, m), 9.73 (1H, s), 11.40 (1H, brs).

EXAMPLE 613-(4-Dimethylaminophenyl)-5-fluoro-8-propoxy-1H-quinolin-4-one

White Powder (Ethyl Acetate)

Melting point 206-207° C.

¹H-NMR (DMSO-d₆) δppm:

1.01 (3H, t, J=7.4 Hz), 1.79-1.88 (2H, m), 2.90 (6H, s), 4.07 (2H, t,J=6.4 Hz), 6.71 (2H, d, J=9.0 Hz), 6.82-6.90 (1H, m), 7.09-7.14 (1H, m),7.45 (2H, d, J=9.0 Hz), 7.76 (1H, s), 11.18 (1H, brs).

EXAMPLE 62 3-(3,4-Dimethoxyphenyl)-5-fluoro-8-propoxy-1H-quinolin-4-one

Pale Red Powder (Ethyl Acetate)

Melting point 217-218° C.

¹H-NMR (DMSO-d₆) δppm:

1.02 (3H, t, J=7.5 Hz), 1.78-1.88 (2H, m), 3.76 (6H, s), 4.07 (2H, t,J=6.4 Hz), 6.85-6.97 (2H, m), 7.08-7.16 (2H, m), 7.30 (1H, s), 7.82 (1H,s), 11.28 (1H, brs).

EXAMPLE 635-Fluoro-3-(6-methoxypyridin-3-yl)-8-propoxy-1H-quinolin-4-one

White Powder (Ethyl Acetate)

Melting point 215-216° C.

¹H-NMR (DMSO-d₆) δppm:

1.02 (3H, t, J=7.5 Hz), 1.77-1.91 (2H, m), 3.86 (3H, s), 4.08 (2H, t,J=6.3 Hz), 6.81-6.96 (2H, m), 7.14-7.19 (1H, m), 7.77-7.99 (2H, m), 8.35(1H, s), 11.39 (1H, brs).

EXAMPLE 643-(2,6-Dimethoxypyridin-3-yl)-5-fluoro-8-propoxy-1H-quinolin-4-one

Pale Red Powder (Ethyl Acetate)

Melting point 198-199° C.

¹H-NMR (DMSO-d₆) δppm:

1.01 (3H, t, J=7.3 Hz), 1.76-1.90 (2H, s), 3.83 (3H, s). 3.89 (3H, s),4.07 (2H, t, J=6.3 Hz), 6.39 (1H, d, J=7.1 Hz), 6.86-6.94 (1H, m),7.13-7.17 (1H, m), 7.68 (1H, d, J=7.1 Hz), 7.81 (1H, s), 11.23 (1H,brs).

EXAMPLE 65 3-(2,5-Dimethoxyphenyl)-5-fluoro-8-propoxy-1H-quinolin-4-one

Pale Red Powder (Ethyl Acetate)

Melting point 156-157° C.

¹H-NMR (DMSO-d₆) δppm:

1.03 (3H, t, J=7.3 Hz), 1.80-1.90 (2H, m), 3.65 (3H, s), 3.71 (3H, s),4.09 (2H, t, J=6.3 Hz), 6.87-6.91 (4H, m), 6.94-6.95 (1H, m), 7.73 (1H,s), 11.18 (1H, brs).

EXAMPLE 668-Cyclopropylmethoxy-1-ethyl-5-fluoro-3-(4-methoxyphenyl)-1H-quinolin-4-one

Brown Powder (Ethyl Acetate-n-hexane)

Melting point 150-152° C.

¹H-NMR (DMSO-d₆) δppm:

0.34-0.38 (2H, m), 0.57-0.64 (2H, m), 1.27-1.39 (4H, m), 3.75 (3H, s),3.92 (2H, d, J=7.2 Hz), 4.60 (2H, q, J=6.8 Hz), 6.91-6.99 (3H, m), 7.17(1H, dd, J=4.5 Hz, J=8.9 Hz), 7.60 (2H, d, J=8.7 Hz), 7.98 (1H, s)

EXAMPLE 675-Fluoro-3-(4-methoxyphenyl)-2-methyl-8-propoxy-1H-quinolin-4-one

5-Fluoro-3-iodo-2-methyl-8-propoxy-1H-quinolin-4-one (400 mg, 1.11mmol), 4-methoxyphenyl boronic acid (504 mg, 3.3 mmol),1,1′-bis(diphenylphosphino)ferrocene dichloro palladium (II)-dichloromethane complex (PdCl₂(DPPF)) (100 mg, 0.12 mmol) and a 2N sodiumcarbonate aqueous solution (1 ml) were added to 1,2-dimethoxyethane (3ml), and the mixture was heated at 170° C. for 10 minutes (microwavereactor). The reaction mixture was cooled to room temperature, andfiltration with Celite was carried out. The filtrate was extracted withdichloromethane, and washed with water. The organic layer was dried overanhydrous magnesium sulfate, and then concentrated under reducedpressure. The residue was then purified by silica gel columnchromatography (dichloromethane:methanol=100:0→40:1). The purifiedproduct was concentrated under reduced pressure, and the residue wasrecrystallized from ethyl acetate to thereby obtain 230 mg of powderywhite 5-fluoro-3-(4-methoxyphenyl)-2-methyl-8-propoxy-1H-quinolin-4-one(yield: 61%).

Melting point 211-212° C.

¹H-NMR (DMSO-d₆) δppm:

0.98 (3H, t, J=7.3 Hz), 1.79-1.90 (2H, m), 2.23 (3H, s), 3.76 (3H, s),4.10 (2H, t, J=6.5 Hz), 6.93-6.95 (2H, m), 7.07-7.09 (2H, m), 7.72-7.73(1H, m), 7.83 (1H, s), 10.50 (1H, brs).

The compounds of the following Examples 68 to 85 were prepared in thesame manner as the above Example 67, using corresponding startingmaterials.

EXAMPLE 68 5-Fluoro-2-methyl-8-propoxy-3-pyridin-3-yl-1H-quinolin-4-one

White Powder (Ethyl Acetate)

Melting point 190-192° C.

¹H-NMR (DMSO-d₆) δppm:

0.99 (3H, t, J=7.5 Hz), 1.77-1.89 (2H, m), 2.27 (3H, s), 4.12 (2H, t,J=6.7 Hz), 6.85-6.93 (1H, m), 7.16-7.21 (1H, m), 7.38-7.43 (1H, m),7.63-7.67 (1H, m). 8.40-8.50 (2H, m), 10.70 (1H, brs).

EXAMPLE 69 5-Fluoro-2-methyl-8-propoxy-3-pyridin-4-yl-1H-quinolin-4-one

White Powder (Ethyl Acetate)

Melting point 265-266° C.

¹H-NMR (DMSO-d₆) δppm:

0.99 (3H, t, J=7.5 Hz), 1.78-1.92 (2H, m), 2.28 (3H, s), 4.12 (2H, t,J=6.8 Hz), 6.86-6.94 (1H, m), 7.17-7.21 (1H, m), 7.25 (2H, d, J=6.0 Hz),8.55 (2H, d, J=6.0 Hz), 10.72 (1H, brs).

EXAMPLE 705-Fluoro-2-methyl-8-propoxy-3-(4-trifluoromethoxyphenyl)-1H-quinolin-4-one

Pale Yellow Powder (Ethyl Acetate)

Melting point 167-168° C.

¹H-NMR (DMSO-d₆) δppm:

0.99 (3H, t, J=7.3 Hz), 1.78-1.92 (2H, m), 2.25 (3H, s), 4.10 (2H, t,J=6.6 Hz), 6.83-6.92 (1H, m), 7.15-7.20 (1H, m), 7.31-7.38 (4H, m),10.64 (1H, brs).

EXAMPLE 713-(4-Ethylphenyl)-5-fluoro-2-methyl-8-propoxy-1H-quinolin-4-one

Pale Red Powder (Ethyl Acetate)

Melting point 221-222° C.

¹H-NMR (DMSO-d₆) δppm:

0.99 (3H, t, J=7.3 Hz), 1.18 (3H, t, J=7.5 Hz), 1.80-1.89 (2H, m), 2.23(3H, s), 2.58 (2H, q, J=7.5 Hz), 4.10 (2H, t, J=6.6 Hz), 6.82-6.89 (1H,m), 7.08-7.22 (5H, m), 10.53 (1H, brs).

EXAMPLE 72 5-Fluoro-2-methyl-8-propoxy-3-thiophen-2-yl-1H-quinolin-4-one

White Powder (Ethyl Acetate)

Melting point 233-234° C.

¹H-NMR (DMSO-d₆) δppm:

0.98 (3H, t, J=7.3 Hz), 1.77-1.89 (2H, m), 2.46 (3H, s), 4.11 (2H, t,J=6.8 Hz), 6.86-7.20 (4H, m), 7.52-7.55 (1H, m), 10.70 (1H, brs).

EXAMPLE 733-(4-Dimethylaminophenyl)-5-fluoro-2-methyl-8-propoxy-1H-quinolin-4-one

White Powder (Ethyl Acetate)

Melting point 255-257° C.

¹H-NMR (DMSO-d₆) δppm:

1.00 (3H, t, J=7.5 Hz), 1.80-1.90 (2H, m), 2.26 (3H, s), 2.91 (6H, s),4.11 (2H, t, J=6.6 Hz), 6.72 (2H, d, J=8.7 Hz), 6.80-6.89 (1H, m), 7.00(2H, d, J=8.7 Hz), 7.11-7.17 (1H, m), 10.45 (1H, brs).

EXAMPLE 745-Fluoro-3-(4-fluorophenyl)-2-methyl-8-propoxy-1H-quinolin-4-one

Pale Brown Powder (Ethyl Acetate)

Melting point 196-197° C.

¹H-NMR (DMSO-d₆) δppm:

1.00 (3H, t, J=7.3 Hz), 1.80-1.91 (2H, m), 2.25 (3H, s), 4.12 (2H, t,6.8 Hz), 6.84-6.92 (1H, m), 7.15-7.29 (5H, m), 10.06 (1H, brs).

EXAMPLE 753-(2,4-Dimethoxyphenyl)-5-fluoro-2-methyl-8-propoxy-1H-quinolin-4-one

Pale Brown Powder (Ethyl Acetate)

Melting point 100-101° C.

¹H-NMR (DMSO-d₆) δppm:

0.99 (3H, t, J=7.5 Hz), 1.80-1.86 (2H, m), 2.11 (3H, s), 3.65 (3H, s),3.78 (3H, s), 4.10 (2H, t, J=6.8 Hz), 6.51-6.59 (2H, m), 6.80-6.94 (2H,m), 7.11-7.17 (1H, m), 10.47 (1H, brs).

EXAMPLE 76 5-Fluoro-3-furan-2-yl-2-methyl-8-propoxy-1H-quinolin-4-one

Pale Brown Powder (Ethyl Acetate)

Melting point 203-204° C.

¹H-NMR (DMSO-d₆) δppm:

0.99 (3H, t, J=7.5 Hz), 1.78-1.89 (2H, m), 2.47 (3H, s), 4.10 (2H, t,J=6.8 Hz), 6.52-6.54 (1H, m), 6.67-6.69 (1H, m), 6.86-6.95 (1H, m),7.15-7.20 (1H, m), 7.67-7.68 (1H, m), 10.66 (1H, m).

EXAMPLE 775-Fluoro-3-(4-methoxyphenyl)-8-propoxy-2-trifluoromethyl-1H-quinolin-4-one

White Powder (n-Hexane-ethyl Acetate)

Melting point 170-171° C.

¹H-NMR (DMSO-d₆) δppm:

1.00 (3H, t, J=7.3 Hz), 1.76-1.90 (2H, m), 3.80 (3H, s), 4.11 (2H, t,J=6.5 Hz), 6.98 (2H, d, J=8.7 Hz), 7.15-7.25 (4H, m), 10.11 (1H, brs).

EXAMPLE 785-Fluoro-3-furan-2-yl-8-propoxy-2-trifluoromethyl-1H-quinolin-4-one

Pale Yellow Powder (n-Hexane-ethyl Acetate)

Melting point 134-136° C.

¹H-NMR (DMSO-d₆) δppm:

0.99 (3H, t, J=7.5 Hz), 1.76-1.90 (2H, m), 4.11 (2H, t, J=6.6 Hz),6.59-6.65 (2H, m), 7.21-7.33 (2H, m), 7.81 (1H, m), 10.08 (1H, brs).

EXAMPLE 793-(4-Dimethylaminophenyl)-5-fluoro-8-propoxy-2-trifluoromethyl-1H-quinolin-4-one

Pale Yellow Powder (n-Hexane-ethyl Acetate)

Melting point 176-177° C.

¹H-NMR (DMSO-d₆) δppm:

1.00 (3H, t, J=7.4 Hz), 1.76-1.91 (2H, m), 2.94 (6H, s), 4.11 (2H, t,J=6.6 Hz), 6.75 (2H, d, J=8.8 Hz), 7.03 (2H, d, J=8.8 Hz), 7.21-7.24(2H, m), 10.00 (1H, brs).

EXAMPLE 803-(4-Ethylphenyl)-5-fluoro-8-propoxy-2-trifluoromethyl-1H-quinolin-4-one

White Powder (n-Hexane-ethyl Acetate)

Melting point 187-188° C.

¹H-NMR (DMSO-d₆) δppm:

1.00 (3H, t, J=7.3 Hz), 1.20 (3H, t, J=7.5 Hz), 1.77-1.91 (2H, m),2.62-2.71 (2H, q, J=7.5 Hz), 4.12 (2H, t, J=6.6 Hz), 7.13-7.29 (6H, m),10.23 (1H, brs).

EXAMPLE 815-Fluoro-3-(4-fluorophenyl)-8-propoxy-2-trifluoromethyl-1H-quinolin-4-one

Brown Powder (n-Hexane-ethyl Acetate)

Melting point 154-155° C.

¹H-NMR (DMSO-d₆) δppm:

1.02 (3H, t, J=7.3 Hz), 1.81-1.89 (2H, m), 4.13 (2H, t, J=6.5 Hz),7.10-7.31 (4H, m), 7.80-7.86 (1H, m), 8.08 (1H, s), 10.24 (1H, brs).

EXAMPLE 825-Fluoro-8-propoxy-3-(4-trifluoromethoxyphenyl)-2-trifluoromethyl-1H-quinolin-4-one

Pale Red Powder (n-Hexane-ethyl Acetate)

Melting point 143-144° C.

¹H-NMR (DMSO-d₆) δppm:

1.00 (3H, t, J=7.3 Hz), 1.77-1.91 (2H, m), 4.12 (2H, t, J=6.6 Hz),7.19-7.54 (6H, m), 10.44 (1H, brs).

EXAMPLE 835-Fluoro-2-isopropyl-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one

White Powder (Ethyl Acetate-n-hexane)

Melting point 195-197° C.

¹H-NMR (DMSO-d₆) δppm:

1.00 (3H, t, J=7.3 Hz), 1.16 (6H, d, J=7.0 Hz), 1.78-1.92 (2H, m),2.86-2.97 (1H, m), 3.77 (3H, s), 4.13 (2H, t, J=6.4 Hz), 6.84-7.22 (6H,m), 8.98 (1H, brs).

EXAMPLE 84 5-Fluoro-3-furan-2-yl-2-isopropyl-8-propoxy-1H-quinolin-4-one

White Powder (Ethyl Acetate-n-hexane)

Melting point 113-114° C.

¹H-NMR (DMSO-d₆) δppm:

0.99 (3H, t, J=7.5 Hz), 1.21 (6H, d, J=7.0 Hz), 1.80-1.89 (2H, m),3.11-3.16 (1H, m), 4.12 (2H, t, J=6.4 Hz), 6.48-6.54 (2H, m), 6.90-6.98(1H, m), 7.20-7.25 (1H, m), 7.69-7.70 (1H, m), 9.29 (1H, brs).

EXAMPLE 855-Fluoro-8-propoxy-3-thiophen-2-yl-2-trifluoromethyl-1H-quinolin-4-one

Pale Yellow Powder (Ethyl Acetate-n-hexane)

Melting point 149-150° C.

¹H-NMR (DMSO-d₆) δppm:

1.00 (3H, t, J=7.4 Hz), 1.76-1.90 (2H, m), 4.11 (2H, t, 6.4 Hz),7.10-7.30 (4H, m), 7.72-7.75 (1H, m), 10.52 (1H, brs).

EXAMPLE 86 5-Fluoro-8-furan-2-yl-3-(4-methoxyphenyl)-1H-quinolin-4-one

8-bromo-5-fluoro-3-(4-methoxyphenyl)-1H-quinolin-4-one (150 mg, 0.43mmol), 2-furan boronic acid (145 mg, 1.3 mmol),1,1′-bis(diphenylphosphino)ferrocene dichloro palladium(II)-dichloromethane complex (PdCl₂(DPPF)) (35 mg, 0.04 mmol) and a 2Nsodium carbonate aqueous solution (1 ml) were added to1,2-dimethoxyethane (3 ml), and the mixture was heated at 180° C. for 10minutes (microwave reactor). After the reaction mixture was cooled toroom temperature, dichloromethane was added, and then filtration withCelite was carried out. The filtrate was extracted with dichloromethaneand washed with water. The organic layer was dried over anhydrousmagnesium sulfate, and then concentrated under reduced pressure. Theresidue was then purified by silica gel column chromatography(dichloromethane). The purified product was concentrated under reducedpressure, and the residue was recrystallized from n-hexane-ethyl acetateto thereby obtain 100 mg of powdery slightly orange5-fluoro-8-furan-2-yl-3-(4-methoxyphenyl)-1H-quinolin-4-one (yield:70%). Melting point 209-211° C.

¹H-NMR (DMSO-d₆) δppm:

3.79 (3H, s), 6.74-6.77 (1H, m), 6.96-7.00 (3H, m), 7.07-7.15 (1H, m),7.55-7.59 (2H, m), 7.81-7.93 (3H, m), 11.00 (1H, brs).

The compounds of the following Examples 87 and 88 were prepared in thesame manner as the above Example 86, using corresponding startingmaterials.

EXAMPLE 875-Fluoro-3-(4-methoxyphenyl)-8-thiophen-3-yl-1H-quinolin-4-one

Pale Yellow Powder (Ethyl Acetate)

Melting point 183-184° C.

¹H-NMR (DMSO-d₆) δppm:

3.76 (3H, s), 6.93-7.09 (3H, m), 7.30-7.32 (1H, m), 7.49-7.54 (3H, m),7.76-7.80 (3H, m), 10.64 (1H, brs).

EXAMPLE 888-Benzo[b]thiophen-2-yl-5-fluoro-3-(4-methoxyphenyl)-1H-quinolin-4-one

Pale Yellow Powder (Ethyl Acetate)

Melting point 276-277° C.

¹H-NMR (DMSO-d₆) δppm:

3.76 (3H, s), 6.84-6.92 (3H, m), 7.30-7.40 (2H, m), 7.62-7.66 (2H, m),7.84-7.99 (5H, m), 11.03 (1H, brs).

EXAMPLE 89 4-(5-Fluoro-4-oxo-8-propoxy-1,4-dihydroquinolin-3-yl)benzoicacid

Methyl 4-(5-fluoro-4-oxo-8-propoxy-1,4-dihydroquinolin-3-yl)benzoate(330 mg, 0.93 mmol) was suspended in a mixed solvent of ethanol (3 ml)and THF (3 ml). A 1.24N lithium hydroxide aqueous solution (2 ml) wasadded, and the mixture was stirred at room temperature for 3 hours.Water was added to the reaction mixture, and then the resulting mixturewas extracted with dichloromethane. The organic layer was washed withwater, dried over magnesium sulfate, and concentrated to dryness underreduced pressure to thereby obtain 300 mg of powdery white4-(5-fluoro-4-oxo-8-propoxy-1,4-dihydroquinolin-3-yl)benzoic acid(yield: 95%).

¹H-NMR (DMSO-d₆) δppm:

1.01-1.07 (3H, t, J=7.3 Hz), 1.80-1.91 (2H, m), 4.09-4.14 (2H, t, J=6.4Hz), 6.85-7.24 (3H, m), 7.75-7.78 (2H, m), 7.92-7.95 (2H, m), 11.51 (1H,brs), 12.84 (1H, brs).

EXAMPLE 905-Fluoro-3-[4-(morpholine-4-carbonyl)phenyl]-8-propoxy-1H-quinolin-4-one

4-(5-Fluoro-4-oxo-8-propoxy-1,4-dihydroquinolin-3-yl)benzoic acid (260mg, 0.76 mmol), morpholine (99.5 mg, 1.14 mmol), WSC (189 mg, 0.99 mmol)and HOBT (151 mg, 0.99 mmol) were added to DMF (10 ml), and the mixturewas stirred at room temperature for 15 hours. The reaction mixture wasconcentrated under reduced pressure, and the residue was then purifiedby silica gel column chromatography (dichloromethane:methanol=30:1). Thepurified product was concentrated under reduced pressure, and theresidue was recrystallized from ethyl acetate to thereby obtain 80 mg ofpowdery white5-fluoro-3-[4-(morpholine-4-carbonyl)phenyl]-8-propoxy-1H-quinolin-4-one(yield: 26%).

Melting point 234-236° C.

¹H-NMR (DMSO-d₆) δppm:

1.02 (3H, t, J=7.4 Hz), 1.80-1.89 (2H, m), 3.40-3.60 (8H, m), 4.09 (2H,t, J=6.5 Hz), 6.89-6.98 (1H, m), 7.16-7.21 (1H, m), 7.41 (2H, d, J=8.3Hz), 7.69 (2H, d, J=8.3 Hz), 7.91 (1H, s), 11.41 (1H, brs).

EXAMPLE 915-Fluoro-3-(4-methoxyphenyl)-1-methyl-8-propoxy-1H-quinolin-4-one

Sodium hydride (60% in oil, 76 mg, 1.9 mmol) was added to a DMF solution(10 ml) of 5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one (400mg, 1.22 mmol). The mixture was stirred at room temperature for 15minutes. Methyl iodide (225 mg, 1.6 mmol) was added thereto, and thenthe resulting mixture was stirred at room temperature for 19 hours.Water and ethyl acetate were added to the reaction mixture to separatethe mixture into two layers. The organic layer was washed with water,dried over anhydrous sodium sulfate, and then concentrated under reducedpressure. The residue was then purified by silica gel columnchromatography (n-hexane:ethyl acetate=1:1). The purified product wasconcentrated under reduced pressure, and the residue was recrystallizedfrom ethyl acetate to thereby obtain 365 mg of powdery pale yellow5-fluoro-3-(4-methoxyphenyl)-1-methyl-8-propoxy-1H-quinolin-4-one(yield: 72%).

Melting point 147-148° C.

¹H-NMR (DMSO-d₆) δppm:

0.98 (3H, t, J=7.5 Hz), 1.77 (2H, m), 3.76 (3H, s), 3.98 (2H, t, J=6.4Hz), 4.08 (3H, s), 6.91-7.01 (3H, m), 7.19-7.24 (1H, m), 7.57-7.61 (2H,m), 7.96 (1H, s).

The compounds of the following Examples 92 to 94 were prepared in thesame manner as the above Example 91, using corresponding startingmaterials.

EXAMPLE 921-Ethyl-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one

White Powder (Ethyl Acetate)

Melting point 123-125° C.

¹H-NMR (DMSO-d₆) δppm:

1.00 (3H, t, J=7.3 Hz), 1.29 (3H, t, J=6.8 Hz), 1.79-1.88 (2H, m), 3.76(3H, s), 4.03 (2H, t, J=6.5 Hz), 4.52 (2H, q, J=6.8 Hz), 6.91-7.02 (3H,m), 7.22-7.27 (1H, m), 7.60 (2H, d, J=8.7 Hz), 8.00 (1H, s).

EXAMPLE 931-(2-Ethoxyethyl)-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one

White Powder (Ethyl Acetate)

Melting point 108-109° C.

¹H-NMR (DMSO-d₆) δppm:

0.96-1.09 (6H, m), 1.77-1.89 (2H, m), 3.65 (2H, t, J=5.0 Hz), 3.78 (3H,s), 4.02 (2H, t, J=6.8 Hz), 4.72 (2H, t, J=5.0 Hz), 6.94-7.04 (3H, m),7.23-7.29 (1H, m), 7.57 (2H, d, J=8.7 Hz), 7.93 (1H, s).

EXAMPLE 941-Cyclopropylmethyl-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one

Pale Yellow Powder (n-Hexane)

Melting point 60-62° C.

¹H-NMR (DMSO-d₆) δppm:

0.36-0.51 (4H, m), 1.07 (3H, t, J=7.4 Hz), 1.26-1.30 (1H, m), 1.86-1.94(2H, m), 4.09 (2H, t, J=6.5 Hz), 6.96-7.08 (3H, m), 7.28-7.33 (1H, m),7.61-7.66 (2H, m), 8.05 (1H, s).

EXAMPLE 95 5-Fluoro-3-(4-hydroxyphenyl)-8-propoxy-1H-quinolin-4-one

A dichloromethane solution (5 ml) of5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one (249 mg, 0.76mmol) was cooled to −10° C. in a methanol-ice bath. A 1N borontribromide (4.08 ml) was added thereto, and the mixture was stirred atroom temperature for 6 hours. Ice water and dichloromethane were addedto the reaction mixture, and the resultant insoluble matter wascollected by filtration. The filtrate was separated and the organiclayer was concentrated under reduced pressure. The residue and thesubstance remaining on the filter were mixed, and the mixture waspurified by silica gel column chromatography(dichloromethane:methanol=60:1→25:1). The purified product wasconcentrated under reduced pressure. Ethyl acetate was added tocrystallize the residue. The crystals were collected by filtration,washed with ethyl acetate, and then dried to thereby obtain 220 mg ofpowdery pale yellow5-fluoro-3-(4-hydroxyphenyl)-8-propoxy-1H-quinolin-4-one (yield: 92%).Melting point 271-272° C.

¹H-NMR (DMSO-d₆) δppm:

1.03 (3H, t, J=7.3 Hz), 1.78-1.87 (2H, m), 4.08 (2H, t, J=6.4 Hz), 6.77(2H, d, J=8.6 Hz), 6.87 (1H, dd, J=8.8 Hz, J=12.1 Hz), 7.12 (1H, dd,J=3.9 Hz, J=8.8 Hz), 7.41 (2H, d, J=8.6 Hz), 7.77 (1H, s), 9.43 (1H,brs), 11.20 (1H, brs).

EXAMPLE 96 5-Fluoro-8-hydroxy-3-(4-hydroxyphenyl)-1H-quinolin-4-one

5-Fluoro-8-methoxy-3-(4-methoxyphenyl)-1H-quinolin-4-one (1.0 g, 3.34mmol) was suspended in dichloromethane (40 ml), and the suspension wascooled to −10° C. in a methanol-ice bath. A 1N boron tribromide (17 ml)was added thereto, and the resulting mixture was stirred at roomtemperature for 15 hours. Ice water and dichloromethane were added tothe reaction mixture, and the resultant insoluble matter was collectedby filtration. The substance remaining on the filter was washed withwater, dried and purified by silica gel column chromatography(dichloromethane:methanol=20:1→8:1→4 ethyl acetate:methanol=4:1). Thepurified product was concentrated under reduced pressure and ethylacetate was then added to crystallize the residue. The crystals werecollected by filtration, washed with ethyl acetate, and dried to therebyobtain 360 mg of powdery pale gray5-fluoro-8-hydroxy-3-(4-hydroxyphenyl)-1H-quinolin-4-one (yield: 40%).

Melting point 303-305° C. (decomposition)

¹H-NMR (DMSO-d₆) δppm:

6.74-6.82 (3H, m), 6.94 (1H, dd, J=4.1 Hz, J=8.5 Hz), 7.41 (2H, d, J=8.3Hz), 7.74 (1H, s), 9.46 (1H, brs), 10.70 (1H, brs), 11.32 (1H, brs).

EXAMPLE 975-Fluoro-3-(4-hydroxy-2-methoxyphenyl)-8-propoxy-1H-quinolin-4-one

Aluminum chloride (108 mg, 0.81 mmol) was added to a dichloromethanesolution (5 ml) of5-fluoro-3-(4-isopropoxy-2-methoxyphenyl)-8-propoxy-1H-quinolin-4-one(120 mg, 0.31 mmol). The mixture was stirred at room temperature for 1hour. Water and dichloromethane were added to the reaction mixture, andseparated. The organic layer was then washed with water. The washedorganic layer was dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was then purified bysilica gel column chromatography (dichloromethane:methanol=10:1). Thepurified product was concentrated under reduced pressure, and theresidue was recrystallized from ethyl acetate to thereby obtain 100 mgof powdery white5-fluoro-3-(4-hydroxy-2-methoxyphenyl)-8-propoxy-1H-quinolin-4-one(yield: 90%). Melting point 251-253° C.

¹H-NMR (DMSO-d₆) δppm:

1.01-1.07 (3H, t, J=7.4 Hz), 1.77-1.88 (2H, m), 3.63 (3H, s), 4.07-4.12(2H, t, J=6.6 Hz), 6.33-6.43 (2H, m), 6.84-6.90 (1H, m), 7.02-7.11 (2H,m), 7.61-7.64 (1H, m), 9.39 (1H, s), 11.07 (1H, brs).

The compound of the following Example 98 was prepared in the same manneras the above Example 97, using corresponding starting materials.

EXAMPLE 985-Fluoro-3-(2-hydroxy-4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one

White Powder (Ethyl Acetate)

Melting point 208-209° C.

¹H-NMR (DMSO-d₆) δppm:

1.02 (3H, t, J=7.5 Hz), 1.81-1.90 (2H, m), 3.73 (3H, s), 4.11 (2H, t,J=6.5 Hz), 6.43-6.51 (2H, m), 6.98-7.06 (1H, m), 7.16-7.25 (2H, m), 7.95(1H, s), 10.23 (1H, s), 11.93 (1H, brs).

EXAMPLE 99 5-Fluoro-8-hydroxy-3-(4-methoxyphenyl)-1H-quinolin-4-one

2N Hydrochloric acid (6.0 ml) was added to an ethanol solution (18 ml)of 5-fluoro-8-methoxymethoxy-3-(4-methoxyphenyl)-1H-quinolin-4-one (350mg, 1.06 mmol). The mixture was stirred at 55° C. for 1 hour. Thestirred mixture was cooled to room temperature, and 1N sodium hydrate(11.6 ml) was added thereto to obtain a pH of 3 to 4. The mixture inwhich pH was adjusted was concentrated under reduced pressure, and theresidue was then purified by silica gel column chromatography(dichloromethane:methanol=50:1→20:1). The purified product wasconcentrated under reduced pressure, and the residue was crystallizedfrom ethanol, collected by filtration, washed with ethanol, and dried tothereby obtain 165 mg of powdery pale dark brown5-fluoro-8-hydroxy-3-(4-methoxyphenyl)-1H-quinolin-4-one (yield: 54%).

Melting point 270-272° C.

¹H-NMR (DMSO-d₆) δppm:

3.75 (3H, s), 6.79 (1H, dd, J=8.5 Hz, J=12.1 Hz), 6.90-6.97 (3H, m),7.53 (2H, d, J=8.6 Hz), 7.77 (1H, s), 10.60 (1H, brs), 11.40 (1H, brs).

EXAMPLE 1005-Fluoro-3-(2-hydroxymethylthiophen-3-yl)-8-propoxy-1H-quinolin-4-one

3-(5-Fluoro-4-oxo-8-propoxy-1,4-dihydroquinolin-3-yl)thiophene-2-carbaldehyde (120 mg, 0.39 mmol) was suspended in ethanol (5ml), and sodium borohydride (19.24 mg) was added to the suspension. Theresulting mixture was stirred at room temperature for 1 hour.Dichloromethane was added to the reaction mixture, which was washed withwater. The organic layer was dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was then purified bysilica gel column chromatography (dichloromethane:methanol=30:1). Thepurified product was concentrated under reduced pressure, and theresidue was recrystallized from ethyl acetate to thereby obtain 110 mgof powdery white5-fluoro-3-(2-hydroxymethylthiophen-3-yl)-8-propoxy-1H-quinolin-4-one(yield: 82%).

Melting point 181-184° C.

¹H-NMR (DMSO-d₆) δppm:

1.01 (3H, t, J=7.3 Hz), 1.79-1.88 (2H, m), 4.07 (2H, t, J=6.4 Hz), 4.47(2H, d, J=5.4 Hz), 5.48 (1H, t, J=5.4 Hz), 6.87-6.96 (1H, m), 7.11-7.19(2H, m), 7.39-7.40 (1H, m), 7.88 (1H, s), 11.36 (1H, brs).

EXAMPLE 1015-Fluoro-8-(3-hydroxypropoxy)-3-(4-methoxyphenyl)-1H-quinolin-4-one

8-(3-Benzyloxypropoxy)-5-fluoro-3-(4-methoxyphenyl)-1H-quinolin-4-one(1.95 g, 4.49 mmol) and a 10% palladium carbon (720 mg) were added toethanol (50 ml). The mixture was stirred at 50° C. for 7.5 hours under ahydrogen atmosphere (1 atmosphere) and subjected to a catalyticreduction. The reaction mixture was cooled to room temperature, andfiltration with Celite was conducted to remove the solvent. The filtratewas concentrated under reduced pressure. The residue was then purifiedby silica gel column chromatography(dichloromethane:methanol=80:1→20:1). The purified product wasconcentrated under reduced pressure, and the residue was concentrated todryness to thereby obtain 820 mg of pale dark brown amorphous solid5-fluoro-8-(3-hydroxypropoxy)-3-(4-methoxyphenyl)-1H-quinolin-4-one(yield: 53%).

¹H-NMR (DMSO-d₆) δppm:

1.92-2.02 (2H, m), 3.65 (2H, t, J=5.9 Hz), 4.20 (2H, t, J=6.2 Hz), 4.59(1H, brs), 6.84-6.95 (3H, m), 7.14 (1H, dd, J=3.9 Hz, J=8.8 Hz), 7.55(2H, d, J=8.7 Hz), 7.80 (1H, s), 11.27 (1H, brs).

The compound of the following Example 102 was prepared in the samemanner as the above Example 101, using corresponding starting materials.

EXAMPLE 1025-Fluoro-8-(2-hydroxypropoxy)-3-(4-methoxyphenyl)-1H-quinolin-4-one

White Powder (Ethyl Acetate)

Melting point 216-218° C.

¹H-NMR (DMSO-d₆) δppm:

1.19 (3H, d, J=6.2 Hz), 3.76 (3H, s), 3.82-4.12 (3H, m), 5.25 (1H, brs),6.84-6.96 (3H, m), 7.12 (1H, dd, J=3.9 Hz, J=8.8 Hz), 7.56 (2H, d, J=8.8Hz), 7.86 (1H, s), 11.20 (1H, brs).

The compounds of the following Examples 103 and 104 were prepared in thesame manner as the above Example 1, using corresponding startingmaterials.

EXAMPLE 103 5-Chloro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one

Pale Brown Powder (Ethyl Acetate)

Melting point 194-196° C.

¹H-NMR (DMSO-d₆) δppm:

1.03 (3H, t, J=7.3 Hz), 1.80-1.87 (2H, m), 3.76 (3H, s), 4.11 (2H, t,J=6.4 Hz), 6.93 (2H, d, J=8.6 Hz), 7.12 (1H, d, J=8.5 Hz), 7.17 (1H, d,J=8.5 Hz), 7.54 (2H, d, J=8.6 Hz), 7.80 (1H, s), 11.23 (1H, brs).

EXAMPLE 1045-Bromo-8-cyclopentyloxy-3-(4-methoxyphenyl)-1H-quinolin-4-one

Pale Brown Powder (Ethanol)

Melting point 213-215° C.

¹H-NMR (DMSO-d₆) δppm:

1.59-1.70 (2H, m), 1.71-2.00 (6H, m), 3.75 (3H, s), 4.97-5.00 (1H, m),6.94 (2H, d, J=8.7 Hz), 7.04 (1H, d, J=8.5 Hz), 7.40 (1H, d, J=8.4 Hz),7.53 (2H, d, J=8.7 Hz), 7.81 (1H, s), 11.20 (1H, brs).

Pharmacological Test 1

Evaluation of Improvement of Mitochondrial Dysfunction Using HumanNeuroblastoma Cell Lines SH-SY5Y Treated with1-methyl-4-phenylpyridinium (MPP⁺)

In human neuroblastoma cell lines SH-SY5Y in which mitochondrialactivity was injured by MPP⁺ treatment (Bollimuntha S. et al., J BiolChem, 280, 2132-2140 (2005) and Shang T. et al., J Biol Chem, 280,34644-34653 (2005)), improvement of the mitochondrial dysfunction wasevaluated on the basis of the measurement value of the mitochondrialoxidation reduction activity using Alamar Blue fluorescent dye after thecompound addition (Nakai M. et al, Exp Neurol, 179, 103-110 (2003)).

The human neuroblastoma cell lines SH-SY5Y were cultured in Dulbecco'sModified Eagle's Medium containing 10% fetal bovine serum (DMEMcontaining 50 units/ml penicillin and 50 μg/ml streptomycin asantibiotics) at 37° C. in the presence of 5% carbon dioxide. Cells werescattered on a poly-D-lysine-coated 96-well black plate at aconcentration of 3-6×10⁴ cells/cm² (medium amount: 100 μl/well), andcultured in the above medium for two days. Further, the medium waschanged to a DMEM containing a 1% N2 supplement (N2-DMEM) or to a medium(100 μl/well) in which 1.5 mM MPP⁺ was dissolved. The cells werecultured therein for 39 to 48 hours, and then subjected to amitochondrial oxidation reduction activity measurement system. A samplecompound that had been previously dissolved in dimethyl sulfoxide (DMSO)was diluted with N2-DMEM, and added in a volume of 10 μl/well 24 hoursbefore the activity measurement (final compound concentration: 0.01 to 1μg/ml).

After removal of the medium by suction, a balanced salt solutioncontaining 10% Alamar Blue (154 mM sodium chloride, 5.6 mM potassiumchloride, 2.3 mM calcium chloride, 1.0 mM magnesium chloride, 3.6 mMsodium bicarbonate, 5 mM glucose, 5 mM HEPES, pH 7.2) was added in avolume of 100 μl/well, and reacted in an incubator at 37° C. for 1 hour.The fluorescent intensity was detected using a fluorescence detector (aproduct of Hamamatsu Photonics K.K., excitation wavelength 530 nm,measurement wavelength 580 nm) to thereby measure the mitochondrialoxidation reduction activity.

The fluorescent intensity of the well of the cells cultured in a mediumcontaining MPP⁺ and in each of the sample compounds was relativelyevaluated based on a 100% fluorescent intensity of the well of the cellscultured in a medium containing DMSO alone (final concentration: 0.1%).When the MPP⁺-induced cell groups exhibited higher florescent intensitythan the cell groups cultured in DMSO alone, the test compound wasjudged to have the improved activity of the mitochondrial dysfunction.

TABLE 1 Evaluation of improvement of mitochondrial dyfunction usinghuman neuroblastoma cell lines SH-SY5Y treated with 1-methyl-4-phenylpyridinium (MPP⁺) Test Compound Concentration FluorescenceIntensity (%) (μg/ml) 0 0.01 0.03 0.1 0.3 1 Compound of 50 51 62 70 6664 Example 1 Compound of 51 54 63 70 78 74 Example 3 Compound of 47 5661 70 72 59 Example 4 Compound of 53 59 71 85 88 83 Example 6 Compoundof 46 52 59 63 74 57 Example 21 Compound of 54 60 70 82 78 84 Example 24Compound of 41 46 56 66 50 24 Example 25 Compound of 46 50 54 69 64 56Example 30 Compound of 38 45 45 57 59 48 Example 31 Compound of 60 69 7477 78 87 Example 34 Compound of 63 75 88 99 95 65 Example 35 Compound of59 63 65 74 71 91 Example 36 Compound of 57 64 73 78 70 61 Example 37Compound of 54 66 67 86 81 78 Example 38 Compound of 53 60 64 76 70 72Example 40 Compound of 49 51 58 71 73 82 Example 47 Compound of 48 53 5667 60 67 Example 53 Compound of 50 53 56 67 66 54 Example 59 Compound of61 70 65 85 80 86 Example 61 Compound of 55 66 62 79 84 80 Example 62Compound of 56 58 65 74 75 85 Example 63 Compound of 56 55 65 74 72 77Example 64 Compound of 57 66 72 83 77 60 Example 66 Compound of 53 56 5767 71 63 Example 70 Compound of 50 56 61 73 78 72 Example 71 Compound of46 52 59 68 61 39 Example 86 Compound of 58 63 66 79 63 51 Example 87Compound of 55 65 69 81 82 83 Example 91 Compound of 55 63 75 77 69 55Example 92 Compound of 58 66 79 86 80 69 Example 93 Compound of 51 56 6769 59 41 Example 94 Compound of 53 56 56 71 73 84 Example 100Pharmacological Test 2Evaluation of Dopaminergic Neuronal Protective Activity Using C57BL/6Mouse Treated with 1-methyl-4-phenyl 1,2,3,6-tetrahydro Pyridine (MPTP)

Using a mouse having MPTP-injured dopaminergic neurons (Chan P. et al.,J Neurochem, 57, 348-351 (1991)), the dopamine neuroprotective activitywas evaluated based on dopamine contents and protein levels of tyrosinehydroxylase (TH) and dopamine transporter (DAT) (i.e., dopaminergicneuronal marker proteins) in the brain corpus striatum region after thecompound administration (Mori A. et al., Neurosci Res, 51, 265-274(2005)).

A male C57BL/6 mouse (provided by Japan Charles River Inc., 10 to 12weeks) was used as a test animal. MPTP was dissolved in a physiologicalsalt solution so that the concentration became 4 mg/ml, and thenadministered to the mouse subcutaneously in a volume of 10 ml/kg. Thetest compound was suspended in a 5% gum arabic/physiological saltsolution (w/v) so that a compound having a concentration of 1 mg/mlcould be obtained. Each of the test compounds or solvents thereof wasorally administered to the mouse after 30 minutes, 24 hours, and 48hours of the MPTP administration. The mouse was decapitated after 72hours of the MPTP administration, the brain was removed, and each sideof the striatum was dissected.

The left striatum was used as a sample to detect the protein level byWestern blot analysis. Each tissue was homogenized in a HEPES buffersucrose solution (0.32 M sucrose, 4 μg/ml pepstatin, 5 μg/ml aprotinin,20 μg/ml trypsin inhibitor, 4 μg/ml leupeptin, 0.2 mMphenylmethanesulfonyl fluoride, 2 mM ethylenediaminetetraacetic acid(EDTA), 2 mM ethylene glycol bis (β aminoethyl ether) tetraacetic acid,20 mM HEPES, pH 7.2), and assayed for protein using a bicinchoninic acidkit for protein assay (provided by Pierce Corporation). Each homogenizedsample, having an equal amount of protein which had been dissolved in aLaemmli sample buffer solution, was subjected to electrophoresis throughsodium dodecyl sulfurate polyacrylamide gels. The protein separated byelectrophoresis was electrically transferred to polyvinylidene fluoridemembranes. The membranes were reacted with specific primary antibody forTH, DAT, and housekeeping proteins, i.e., the αl subunit ofNa⁺/K⁺-ATPase and actin (Na⁺/K⁺-ATPase, a product of UpStateBiotechnology Inc.; others are products of Chemi-Con Corporation).Subsequently, a horseradish peroxidase-labeled secondary antibody (aproduct of Amersham K.K.) for each primary antibody was fixed, and thechemiluminescence associated with enzyme activity of peroxidase wasdetected using X-ray film. The density of the protein band on the filmwas analyzed using a densitometer (a product of Bio-rad LaboratoriesInc.) to obtain the TH value relative to Na⁺/K⁺-ATPase and the DAT valuerelative to actin.

The right striatum, the tissue weight of which was measured immediatelyafter dissection, was used as an analysis sample for determining thedopamine content. Each tissue was homogenized in a 0.1 N perchloric acidsolution containing isoproterenol as an internal standard substance ofthe measurement, using an ultrasonic homogenizer while being cooled withice. The supernatant obtained from 20,000 g of homogenate that had beencentrifuged at 4° C. for 15 minutes was subjected to a high performanceliquid chromatography with a reversed phase column (a product of EicomCorporation). A mobile phase 15% methanol 0.1 M citric acid/0.1 M sodiumacetate buffer solution (containing 190 mg/l 1-sodium octane sulfonate,5 mg/l EDTA, pH 3.5) was flowed at a rate of 0.5 ml/min, and thedopamine peak of each sample was detected using an electrochemicaldetector (applied voltage +750 mV vs. Ag/AgCl, a product of EicomCorporation). With reference to the identified dopamine peak, thedopamine content per tissue weight was calculated in each sample usinganalysis software (a product of Gilson Inc.).

In both analyses, the value of the sample derived from the MPTP-inducedmice in which only the test compound or the solvent was administered wasexpressed relative to the value of the sample derived from the micewithout MPTP treatment (100%). Values were analyzed statistically usinga nonclinical statistical analysis system. Values of significanceprobability <0.05 were defined as statistically significant. In theMPTP-induced mice, when the test drug group showed an increase inprotein level compared to the solvent group, and a significantdifference was observed between these groups at t-assay, the test drugwas judged to have dopamine neuroprotective activity.

The invention claimed is:
 1. A pharmaceutical composition, comprising: aquinolone compound represented by General Formula (1) or a salt thereofas an active ingredient, and a pharmaceutically acceptable carrier:

wherein R₁ represents a hydrogen atom, a lower alkyl group, a cyclo C₃₋₈alkyl lower alkyl group, or a lower alkoxy lower alkyl group; R₂represents a hydrogen atom, a lower alkyl group, or ahalogen-substituted lower alkyl group; R₃ represents a phenyl group, afuryl group, a thienyl group, or a pyridyl group, each of the groupsoptionally being substituted with one or more groups selected from thegroup consisting of the following (1) to (16) on the aromatic orheterocyclic ring represented by the above R₃: (1) lower alkyl groups,(2) lower alkoxy groups, (3) halogen-substituted lower alkoxy groups,(4) a phenoxy group, (5) lower alkylthio groups, (6) a hydroxy group,(7) hydroxy lower alkyl groups, (8) halogen atoms, (9) lower alkanoylgroups, (10) lower alkoxycarbonyl groups, (11) amino groups optionallysubstituted with one or more lower alkyl groups, (12) carbamoyl groupsoptionally substituted with one or more lower alkyl groups, (13) cycloC₃₋₈ alkyl lower alkoxy groups, (14) pyrrolidinyl carbonyl groups, (15)morpholinyl carbonyl groups, and (16) a carboxyl group; R₄ represents ahalogen atom; R₅ represents a hydrogen atom or a halogen atom; R₆represents a hydrogen atom; and R₇ represents any one of groups (1) to(15) below; (1) a hydroxy group, (2) a halogen atom, (3) a lower alkoxygroup, (4) a halogen-substituted lower alkoxy group, (5) a hydroxy loweralkoxy group, (6) a lower alkoxy lower alkoxy group, (7) an amino groupoptionally substituted with one or more members selected from the groupconsisting of lower alkyl groups, lower alkoxy lower alkyl groups, andcyclo C₃₋₈ alkyl groups, (8) an amino lower alkoxy group optionallysubstituted on the amino group with one or more members selected fromthe group consisting of lower alkyl groups, lower alkanoyl groups, loweralkyl sulfonyl groups, and carbamoyl groups optionally substituted withone or more lower alkyl groups, (9) a cyclo C₃₋₈ alkyloxy group, (10) acyclo C₃₋₈ alkyl lower alkoxy group, (11) a tetrahydrofuryl lower alkoxygroup, (12) a lower alkylthio group, (13) a heterocyclic group selectedfrom the group consisting of morpholinyl groups, pyrrolidinyl groups,furyl groups, thienyl groups, and benzothienyl groups, (14) a phenyllower alkoxy lower alkoxy group, and (15) a pyrrolidinyl carbonyl group.2. The pharmaceutical composition according to claim 1, wherein R₁represents a hydrogen atom or a lower alkyl group; R₂ represents ahydrogen atom or a lower alkyl group; R₃ represents a phenyl group or apyridyl group, each of the groups optionally being substituted with oneor two groups selected from the group consisting of the following (1),(2), (6), and (8) on the aromatic or heterocyclic ring represented bythe above R₃: (1) lower alkyl groups, (2) lower alkoxy groups, (6) ahydroxy group, and (8) halogen atoms; R₄ represents a halogen atom; R₅represents a hydrogen atom; R₆ represents a hydrogen atom; and R₇represents any one of groups (3), (4), and (7) below: (3) a lower alkoxygroup, (4) a halogen-substituted lower alkoxy group, and (7) an aminogroup optionally substituted with one or two lower alkyl groups.
 3. Thepharmaceutical composition according to claim 2, wherein the compound ofGeneral Formula (1) is selected from the group consisting of:5-fluoro-3-(4-methoxyphenyl)-2-methyl-8-propoxy-1H-quinolin-4-one,5-fluoro-3-(4-methoxyphenyl)-1-methyl-8-propoxy-1H-quinolin-4-one,3-(2,4-dimethoxyphenyl)-5-fluoro-8-propoxy-1H-quinolin-4-one,5-fluoro-8-isopropoxy-3-(4-methoxyphenyl)-1H-quinolin-4-one,3-(2,4-dichlorophenyl)-5-fluoro-8-propoxy-1H-quinolin-4-one,8-ethoxy-5-fluoro-3-(4-methoxyphenyl)-1H-quinolin-4-one,5-fluoro-3-(4-methoxy-2-methylphenyl)-8-propoxy-1H-quinolin-4-one,5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one,5-fluoro-3-(2-fluoro-4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one,5-fluoro-3-(4-hydroxyphenyl)-8-propoxy-1H-quinolin-4-one,8-cyclopropylmethoxy-5-fluoro-3-(4-methoxyphenyl)-1H-quinolin-4-one,5-fluoro-8-propoxy-3-pyridin-4-yl-1H-quinolin-4-one,5-fluoro-3-(4-methoxyphenyl)-8-(N-methyl-N-propylamino)-1H-quinolin-4-one,and5-fluoro-3-(4-methoxyphenyl)-8-(4,4,4-trifluorobutoxy)-1H-quinolin-4-one.4. A method for treating Alzheimer's disease, comprising: administeringa quinolone compound represented by General Formula (1) or a saltthereof to a human or animal:

wherein R₁ represents a hydrogen atom, a lower alkyl group, a cyclo C₃₋₈alkyl lower alkyl group, or a lower alkoxy lower alkyl group; R₂represents a hydrogen atom, a lower alkyl group, or ahalogen-substituted lower alkyl group; R₃ represents a phenyl group, afuryl group, a thienyl group, or a pyridyl group, each of the groupsoptionally being substituted with one or more groups selected from thegroup consisting of the following (1) to (16) on the aromatic orheterocyclic ring represented by the above R₃: (1) lower alkyl groups,(2) lower alkoxy groups, (3) halogen-substituted lower alkoxy groups,(4) a phenoxy group, (5) lower alkylthio groups, (6) a hydroxy group,(7) hydroxy lower alkyl groups, (8) halogen atoms, (9) lower alkanoylgroups, (10) lower alkoxycarbonyl groups, (11) amino groups optionallysubstituted with one or more lower alkyl groups, (12) carbamoyl groupsoptionally substituted with one or more lower alkyl groups, (13) cycloC₃₋₈ alkyl lower alkoxy groups, (14) pyrrolidinyl carbonyl groups, (15)morpholinyl carbonyl groups, and (16) a carboxyl group; R₄ represents ahalogen atom; R₅ represents a hydrogen atom or a halogen atom; R₆represents a hydrogen atom; and R₇ represents any one of groups (1) to(15) below; (1) a hydroxy group, (2) a halogen atom, (3) a lower alkoxygroup, (4) a halogen-substituted lower alkoxy group, (5) a hydroxy loweralkoxy group, (6) a lower alkoxy lower alkoxy group, (7) an amino groupoptionally substituted with one or more members selected from the groupconsisting of lower alkyl groups, lower alkoxy lower alkyl groups, andcyclo C₃₋₈ alkyl groups, (8) an amino lower alkoxy group optionallysubstituted on the amino group with one or more members selected fromthe group consisting of lower alkyl groups, lower alkanoyl groups, loweralkyl sulfonyl groups, and carbamoyl groups optionally substituted withone or more lower alkyl groups, (9) a cyclo C₃₋₈ alkyloxy group, (10) acyclo C₃₋₈ alkyl lower alkoxy group, (11) a tetrahydrofuryl lower alkoxygroup, (12) a lower alkylthio group, (13) a heterocyclic group selectedfrom the group consisting of morpholinyl groups, pyrrolidinyl groups,furyl groups, thienyl groups, and benzothienyl groups, (14) a phenyllower alkoxy lower alkoxy group, and (15) a pyrrolidinyl carbonyl group.5. The method for treating Alzheimer's disease according to claim 4,wherein R₁ represents a hydrogen atom or a lower alkyl group; R₂represents a hydrogen atom or a lower alkyl group; R₃ represents aphenyl group or a pyridyl group, each of the groups optionally beingsubstituted with one or two groups selected from the group consisting ofthe following (1), (2), (6), and (8) on the aromatic or heterocyclicring represented by the above R₃: (1) lower alkyl groups, (2) loweralkoxy groups, (6) a hydroxy group, and (8) halogen atoms; R₄ representsa halogen atom; R₅ represents a hydrogen atom; R₆ represents a hydrogenatom; and R₇ represents any one of groups (3), (4), and (7) below: (3) alower alkoxy group, (4) a halogen-substituted lower alkoxy group, and(7) an amino group optionally substituted with one or two lower alkylgroups.
 6. The method for treating Alzheimer's disease according toclaim 4, wherein the quinolone compound represented by General Formula(1) is selected from the group consisting of:5-fluoro-3-(4-methoxyphenyl)-2-methyl-8-propoxy-1H-quinolin-4-one,5-fluoro-3-(4-methoxyphenyl)-1-methyl-8-propoxy-1H-quinolin-4-one,3-(2,4-dimethoxyphenyl)-5-fluoro-8-propoxy-1H-quinolin-4-one,5-fluoro-8-isopropoxy-3-(4-methoxyphenyl)-1H-quinolin-4-one,3-(2,4-dichlorophenyl)-5-fluoro-8-propoxy-1H-quinolin-4-one,8-ethoxy-5-fluoro-3-(4-methoxyphenyl)-1H-quinolin-4-one,5-fluoro-3-(4-methoxy-2-methylphenyl)-8-propoxy-1H-quinolin-4-one,5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one,5-fluoro-3-(2-fluoro-4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one,5-fluoro-3-(4-hydroxyphenyl)-8-propoxy-1H-quinolin-4-one,8-cyclopropylmethoxy-5-fluoro-3-(4-methoxyphenyl)-1H-quinolin-4-one,5-fluoro-8-propoxy-3-pyridin-4-yl-1H-quinolin-4-one,5-fluoro-3-(4-methoxyphenyl)-8-(N-methyl-N-propylamino)-1H-quinolin-4-one,and5-fluoro-3-(4-methoxyphenyl)-8-(4,4,4-trifluorobutoxy)-1H-quinolin-4-one.